Proteopedia - User contributions [en]

Vpr protein

2018-04-10T06:08:26Z

Elia Shlush:

<StructureSection load='1m8l' size='300' side='right' caption='NMR structure of the HIV-1 Regulatory Protein Vpr' scene=''>

== Function ==
'''Vpr protein''' (Vpr) or '''viral protein R''' is a 96 amino acid protein which encoded by the human Immunodeﬁciency virus type 1 ([[HIV-1]]). HIV-1 genome includes nine genes, six of them are accessory proteins, including ''vpr''. Vpr has several roles in the progression of acquired immunodeficiency syndrome ([https://en.wikipedia.org/wiki/AIDS AIDS]) disease, including regulation the HIV-1 pre-integration complex ([https://en.wikipedia.org/wiki/Pre-integration_complex PIC]) nuclear import and virus replication in non-dividing macrophages<ref name='Morellet2003'>PMID:12614620</ref>. Moreover, Vpr prevents mitosis of dividing infect cells by blockade at G2 phase, when the viral promoter is more active, and induced apoptosis of these cells in G1 and M phase. Both the activities of cell cycle arrest and induce apoptosis has proven to be independence by mutations that can cause only one of these affects<ref name='Gonzalez2017'>PMID:28075409</ref>.

=== Vpr induce cell cycle arrest by recruits cellular targets for degradation<ref name='Wu2016'>PMID:27571178</ref> ===
One phenotype of Vpr expression is the induction of cell cycle arrest in G2 phase. This arrest executes by engaging of damage–binding protein 1 (DDB1) and CUL4A-associated factor 1 (DCAF1) to Vpr. DCAF1 is a substrate receptor of the Cullin4–RING E3 ubiquitin ligase (CRL4) of the host ubiquitin–proteasome-mediated protein degradation pathway. Mutations in Vpr that abolish its interaction with DCAF1, or silencing of DCAF1, eliminate cell-cycle arrest. The crystal structure of <scene name='75/750237/Vpr_ddb1_dcaf1_ung2/2'>DDB1–DCAF1–HIV-1–Vpr–uracil-DNA glycosylase (UNG2) complex</scene> elucidate the molecular mechanism in which Vpr inhibits UNG2 enzymatic activity and send it for degradation:
DCAF1 WD40 domain <scene name='75/750237/Dcaf1_vpr/1'>binds to Vpr</scene> by its N-terminus and α3 helix. In addition, <scene name='75/750237/Dcaf1_ddb1/1'>DCAF1 is anchored into DDB1</scene> by a helix-loop-helix motif. These motifs are commonly found in substrate receptor proteins that bind to DDB1. Finally, Vpr uses structural mimicry to DNA to <scene name='75/750237/Vpr_ung2/1'>engages UNG2</scene>. It interacts with UNG2 by residues in the hydrophobic cleft and an insert loop (residues 266–283), which mimics the phosphate backbone in the DNA. When interacts with DNA, UNG2 Leu272 residue uses to insert into the minor groove. The importance of Leu272 residue to UNG2-Vpr interaction was demonstrated by mutagenesis. Thus, Vpr recruite the CRL4–DCAF1 E3 ubiquitin ligase and targets cellular substrates for degradation. The reason for UNG2 degradation is not clear yet. However, their is a possibility that UNG2 exerts a negative effect on HIV-1 replication.

== Disease ==
HIV-1 retrovirus is the cause of AIDS disease. HIV-1 is a RNA virus which copy its genome to the host-cell genome in infect cells. HIV-1 infects activated CD4 immune cells and macrophages. When the disease is expressing in carriers, the progressive depletion of CD4 T cells causes immunodeficiency<ref name='Emerman1996'>PMID:8805364</ref>.
For more details about AIDS disease see {{Wikipedia|AIDS}}
For details about another HIV-1 components and its replication pathway see [[HIV and accessory proteins]].

== Relevance ==
As of now (October 2017), the currently approved anti-HIV drugs target the Pol and Env encoded proteins. These drugs are effective in reducing viral replication. Thus, because of spontaneous mutations that occur during viral replication, drug resistance is evolve<ref>PMID:28681118</ref>. Understanding of Vpr structure and molecular mechanism may facilitate the design of HIV-1 antiviral therapy by its inhibition. Deletion of both ''vpr'' and ''vpx'' genes in SIV, which their protein products in SIV combine Vpr function in HIV-1, eliminate virus replication<ref name='Emerman1996'/>. The multiple significant functions that Vpr fills in HIV-1 replication makes it an attractive candidate for antiviral therapy<ref name='Gonzalez2017'/>.

== Structural highlights<ref>PMID:12614620</ref> ==
Vpr structure is characterized by three well-defined α-helices: 17–33, 38–50 and 56–77 surrounded by flexible N and C-terminal domains. Vpr has been determined by NMR in the presence of 30% TFE several times, in [[1esx]], [[1vpc]] and [[1ceu]] structures. TFE is known to stabilize secondary structures and to prevent interactions between hydrophobic cores. However, the result was <scene name='75/750237/Vpr/1'>less globular structure</scene> than what it could be in reality. So, another NMR solution of Vpr was determined in the presence 10–30% of CD3CN, a less hydrophobic solvent, and in pure water. <scene name='75/750237/Vpr/2'>In this structure</scene> ([[1m8l]]), the structure folding around a hydrophobic core was improved, and can explain the binding properties of Vpr.

== Conservation ==
Vpr is <scene name='75/750237/Conservation/3'>highly conserved</scene> in HIV and simian immunodeficiency virus (SIV), similar retrovirus which infects non-human primates<ref name='Morellet2003'/>. In addition, all primate lentiviruses has Vpr gene whose protein product has highly conserved motifs. HIV-2 and SIVsm lentiviruses have additionally gene - ''vpx''. In these lentiviruses, Vpr and Vpx executes together the roles which HIV-1 Vpr perform. Vpr and Vpx has low conservation between them<ref name='Emerman1996'/>. However, Vpr and Vpx families of proteins use related structural regions to bind and recruit cellular targets to the E3 ligase complex for degradation by the proteasome<ref name='Wu2016'/>. 
[[Image:Consurf_key_small.gif|200px|right]]

</StructureSection>

== 3D Structures of Vpr protein ==

Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}

[[1m8l]] – Vpr - NMR - HIV-1 
[[1esx]] - synthetic Vpr - NMR - HIV-1 
[[5jk7]] – Vpr + DDB1 + DCAF-1 + UNG2 – X-ray solution - HIV-1 
[[1x9v]] – Dimeric structure of the Vpr C-terminal domain - NMR 
[[1vpc]] - C-terminal domain of Vpr - NMR - HIV-1 
[[1fi0]] - Vpr residues 13-33 in micelles - NMR - HIV-1 
[[1bde]] - NMR solution of Vpr peptides connected to cell cycle arrest and nuclear provirus transfer 
[[5b56]] - Importin subunit alpha-1 + Vpr C-terminal domain - crystallographic analysis 
[[1kzs]], [[1kzt]], [[1kzv]] - Vpr residues 34-51 - NMR - HIV-1 
[[1dsj]] - Vpr residues 50-75 - NMR - HIV-1 
[[1ceu]] - Vpr N-terminal domain - NMR - HIV-1 
[[1dsk]] - Vpr residues 59-86 - NMR - HIV-1 

== References ==
<references/>
[[Category:Topic Page]]

Vpr protein

2018-04-10T06:06:22Z

Elia Shlush:

<StructureSection load='1m8l' size='300' side='right' caption='NMR structure of the HIV-1 Regulatory Protein Vpr' scene=''>

== Function ==
'''Vpr protein''' (Vpr) or '''viral protein R''' is a 96 amino acid protein which encoded by the human Immunodeﬁciency virus type 1 ([[HIV-1]]). HIV-1 genome includes nine genes, six of them are accessory proteins, including ''vpr''. Vpr has several roles in the progression of acquired immunodeficiency syndrome ([https://en.wikipedia.org/wiki/AIDS AIDS]) disease, including regulation the HIV-1 pre-integration complex ([https://en.wikipedia.org/wiki/Pre-integration_complex PIC]) nuclear import and virus replication in non-dividing macrophages<ref name='Morellet2003'>PMID:12614620</ref>. Moreover, Vpr prevents mitosis of dividing infect cells by blockade at G2 phase, when the viral promoter is more active, and induced apoptosis of these cells in G1 and M phase. Both the activities of cell cycle arrest and induce apoptosis has proven to be independence by mutations that can cause only one of these affects<ref name='Gonzalez2017'>PMID:28075409</ref>.

=== Vpr induce cell cycle arrest by recruits cellular targets for degradation<ref name='Wu2016'>PMID:27571178</ref> ===
One phenotype of Vpr expression is the induction of cell cycle arrest in G2 phase. This arrest executes by engaging of damage–binding protein 1 (DDB1) and CUL4A-associated factor 1 (DCAF1) to Vpr. DCAF1 is a substrate receptor of the Cullin4–RING E3 ubiquitin ligase (CRL4) of the host ubiquitin–proteasome-mediated protein degradation pathway. Mutations in Vpr that abolish its interaction with DCAF1, or silencing of DCAF1, eliminate cell-cycle arrest. The crystal structure of <scene name='75/750237/Vpr_ddb1_dcaf1_ung2/2'>DDB1–DCAF1–HIV-1–Vpr–uracil-DNA glycosylase (UNG2) complex</scene> elucidate the molecular mechanism in which Vpr inhibits UNG2 enzymatic activity and send it for degradation:
DCAF1 WD40 domain <scene name='75/750237/Dcaf1_vpr/1'>binds to Vpr</scene> by its N-terminus and α3 helix. In addition, <scene name='75/750237/Dcaf1_ddb1/1'>DCAF1 is anchored into DDB1</scene> by a helix-loop-helix motif. These motifs are commonly found in substrate receptor proteins that bind to DDB1. Finally, Vpr uses structural mimicry to DNA to <scene name='75/750237/Vpr_ung2/1'>engages UNG2</scene>. It interacts with UNG2 by residues in the hydrophobic cleft and an insert loop (residues 266–283), which mimics the phosphate backbone in the DNA. When interacts with DNA, UNG2 Leu272 residue uses to insert into the minor groove. The importance of Leu272 residue to UNG2-Vpr interaction was demonstrated by mutagenesis. Thus, Vpr recruite the CRL4–DCAF1 E3 ubiquitin ligase and targets cellular substrates for degradation. The reason for UNG2 degradation is not clear yet. However, their is a possibility that UNG2 exerts a negative effect on HIV-1 replication.

== Disease ==
HIV-1 retrovirus is the cause of AIDS disease. HIV-1 is a RNA virus which copy its genome to the host-cell genome in infect cells. HIV-1 infects activated CD4 immune cells and macrophages. When the disease is expressing in carriers, the progressive depletion of CD4 T cells causes immunodeficiency<ref name='Emerman1996'>PMID:8805364</ref>.
For more details about AIDS disease see {{Wikipedia|AIDS}}
For details about another HIV-1 components and its replication pathway see [[HIV and accessory proteins]].

== Relevance ==
As of now (October 2017), the currently approved anti-HIV drugs target the Pol and Env encoded proteins. These drugs are effective in reducing viral replication. Thus, because of spontaneous mutations that occur during viral replication, drug resistance is evolve<ref>PMID:28681118</ref>. Understanding of Vpr structure and molecular mechanism may facilitate the design of HIV-1 antiviral therapy by its inhibition. Deletion of both ''vpr'' and ''vpx'' genes in SIV, which their protein products in SIV combine Vpr function in HIV-1, eliminate virus replication<ref name='Emerman1996'/>. The multiple significant functions that Vpr fills in HIV-1 replication makes it an attractive candidate for antiviral therapy<ref name='Gonzalez2017'/>.

== Structural highlights<ref>PMID:12614620</ref> ==
Vpr structure is characterized by three well-defined α-helices: 17–33, 38–50 and 56–77 surrounded by flexible N and C-terminal domains. Vpr has been determined by NMR in the presence of 30% TFE several times, in [[1esx]], [[1vpc]] and [[1ceu]] structures. TFE is known to stabilize secondary structures and to prevent interactions between hydrophobic cores. However, the result was <scene name='75/750237/Vpr/1'>less globular structure</scene> than what it could be in reality. So, another NMR solution of Vpr was determined in the presence 10–30% of CD3CN, a less hydrophobic solvent, and in pure water. <scene name='75/750237/Vpr/2'>In this structure</scene> ([[1m8l]]), the structure folding around a hydrophobic core was improved, and can explain the binding properties of Vpr.

== Conservation ==
Vpr is <scene name='75/750237/Conservation/3'>highly conserved</scene> in HIV and simian immunodeficiency virus (SIV), similar retrovirus which infects non-human primates<ref name='Morellet2003'/>. In addition, all primate lentiviruses has Vpr gene whose protein product has highly conserved motifs. HIV-2 and SIVsm lentiviruses have additionally gene - Vpx. In these lentiviruses, Vpr and Vpx executes together the roles which HIV-1 Vpr perform. Vpr and Vpx has low conservation between them<ref name='Emerman1996'/>. However, Vpr and Vpx families of proteins use related structural regions to bind and recruit cellular targets to the E3 ligase complex for degradation by the proteasome<ref name='Wu2016'/>. 
[[Image:Consurf_key_small.gif|200px|right]]

</StructureSection>

== 3D Structures of Vpr protein ==

Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}

[[1m8l]] – Vpr - NMR - HIV-1 
[[1esx]] - synthetic Vpr - NMR - HIV-1 
[[5jk7]] – Vpr + DDB1 + DCAF-1 + UNG2 – X-ray solution - HIV-1 
[[1x9v]] – Dimeric structure of the Vpr C-terminal domain - NMR 
[[1vpc]] - C-terminal domain of Vpr - NMR - HIV-1 
[[1fi0]] - Vpr residues 13-33 in micelles - NMR - HIV-1 
[[1bde]] - NMR solution of Vpr peptides connected to cell cycle arrest and nuclear provirus transfer 
[[5b56]] - Importin subunit alpha-1 + Vpr C-terminal domain - crystallographic analysis 
[[1kzs]], [[1kzt]], [[1kzv]] - Vpr residues 34-51 - NMR - HIV-1 
[[1dsj]] - Vpr residues 50-75 - NMR - HIV-1 
[[1ceu]] - Vpr N-terminal domain - NMR - HIV-1 
[[1dsk]] - Vpr residues 59-86 - NMR - HIV-1 

== References ==
<references/>
[[Category:Topic Page]]

Vpr protein

2018-04-10T06:04:40Z

Elia Shlush:

<StructureSection load='1m8l' size='300' side='right' caption='NMR structure of the HIV-1 Regulatory Protein Vpr' scene=''>

== Function ==
'''Vpr protein''' (Vpr) or '''viral protein R''' is a 96 amino acid protein which encoded by the human Immunodeﬁciency virus type 1 ([[HIV-1]]). HIV-1 genome includes nine genes, six of them are accessory proteins, including ''vpr''. Vpr has several roles in the progression of acquired immunodeficiency syndrome ([https://en.wikipedia.org/wiki/AIDS AIDS]) disease, including regulation the HIV-1 pre-integration complex ([https://en.wikipedia.org/wiki/Pre-integration_complex PIC]) nuclear import and virus replication in non-dividing macrophages<ref name='Morellet2003'>PMID:12614620</ref>. Moreover, Vpr prevents mitosis of dividing infect cells by blockade at G2 phase, when the viral promoter is more active, and induced apoptosis of these cells in G1 and M phase. Both the activities of cell cycle arrest and induce apoptosis has proven to be independence by mutations that can cause only one of these affects<ref name='Gonzalez2017'>PMID:28075409</ref>.

=== Vpr induce cell cycle arrest by recruits cellular targets for degradation<ref name='Wu2016'>PMID:27571178</ref> ===
One phenotype of Vpr expression is the induction of cell cycle arrest in G2 phase. This arrest executes by engaging of damage–binding protein 1 (DDB1) and CUL4A-associated factor 1 (DCAF1) to Vpr. DCAF1 is a substrate receptor of the Cullin4–RING E3 ubiquitin ligase (CRL4) of the host ubiquitin–proteasome-mediated protein degradation pathway. Mutations in Vpr that abolish its interaction with DCAF1, or silencing of DCAF1, eliminate cell-cycle arrest. The crystal structure of <scene name='75/750237/Vpr_ddb1_dcaf1_ung2/2'>DDB1–DCAF1–HIV-1–Vpr–uracil-DNA glycosylase (UNG2) complex</scene> elucidate the molecular mechanism in which Vpr inhibits UNG2 enzymatic activity and send it for degradation:
DCAF1 WD40 domain <scene name='75/750237/Dcaf1_vpr/1'>binds to Vpr</scene> by its N-terminus and α3 helix. In addition, <scene name='75/750237/Dcaf1_ddb1/1'>DCAF1 is anchored into DDB1</scene> by a helix-loop-helix motif. These motifs are commonly found in substrate receptor proteins that bind to DDB1. Finally, Vpr uses structural mimicry to DNA to <scene name='75/750237/Vpr_ung2/1'>engages UNG2</scene>. It interacts with UNG2 by residues in the hydrophobic cleft and an insert loop (residues 266–283), which mimics the phosphate backbone in the DNA. When interacts with DNA, UNG2 Leu272 residue uses to insert into the minor groove. The importance of Leu272 residue to UNG2-Vpr interaction was demonstrated by mutagenesis. Thus, Vpr recruite the CRL4–DCAF1 E3 ubiquitin ligase and targets cellular substrates for degradation. The reason for UNG2 degradation is not clear yet. However, their is a possibility that UNG2 exerts a negative effect on HIV-1 replication.

== Disease ==
HIV-1 retrovirus is the cause of AIDS disease. HIV-1 is a RNA virus which copy its genome to the host-cell genome in infect cells. HIV-1 infects activated CD4 immune cells and macrophages. When the disease is expressing in carriers, the progressive depletion of CD4 T cells causes immunodeficiency<ref name='Emerman1996'>PMID:8805364</ref>.
For more details about AIDS disease see {{Wikipedia|AIDS}}
For details about another HIV-1 components and its replication pathway see [[HIV and accessory proteins]].

== Relevance ==
As of now (October 2017), the currently approved anti-HIV drugs target the Pol and Env encoded proteins. These drugs are effective in reducing viral replication. Thus, because of spontaneous mutations that occur during viral replication, drug resistance is evolve<ref>PMID:28681118</ref>. Understanding of Vpr structure and molecular mechanism may facilitate the design of HIV-1 antiviral therapy by its inhibition. Deletion of both ''vpr'' and ''vpx'' genes in SIV, which their protein products in SIV combine Vpr function in HIV-1, eliminate virus replication<ref name='Emerman1996'/>. The multiple significant functions that Vpr fills in HIV-1 replication makes it an attractive candidate for antiviral therapy<ref name='Gonzalez2017'/>.

== Structural highlights<ref>PMID:12614620</ref> ==
Vpr structure is characterized by three well-defined α-helices: 17–33, 38–50 and 56–77 surrounded by flexible N and C-terminal domains. Vpr have been determined by NMR in the presence of 30% TFE several times, in [[1esx]], [[1vpc]] and [[1ceu]] structures. TFE is known to stabilize secondary structures and to prevent interactions between hydrophobic cores. However, the result was <scene name='75/750237/Vpr/1'>less globular structure</scene> than what it could be in reality. So, another NMR solution of Vpr was determined in the presence 10–30% of CD3CN, a less hydrophobic solvent, and in pure water. <scene name='75/750237/Vpr/2'>In this structure</scene> ([[1m8l]]), the structure folding around a hydrophobic core was improved, and can explain the binding properties of Vpr.

== Conservation ==
Vpr is <scene name='75/750237/Conservation/3'>highly conserved</scene> in HIV and simian immunodeficiency virus (SIV), similar retrovirus which infects non-human primates<ref name='Morellet2003'/>. In addition, all primate lentiviruses has Vpr gene whose protein product has highly conserved motifs. HIV-2 and SIVsm lentiviruses have additionally gene - Vpx. In these lentiviruses, Vpr and Vpx executes together the roles which HIV-1 Vpr perform. Vpr and Vpx has low conservation between them<ref name='Emerman1996'/>. However, Vpr and Vpx families of proteins use related structural regions to bind and recruit cellular targets to the E3 ligase complex for degradation by the proteasome<ref name='Wu2016'/>. 
[[Image:Consurf_key_small.gif|200px|right]]

</StructureSection>

== 3D Structures of Vpr protein ==

Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}

[[1m8l]] – Vpr - NMR - HIV-1 
[[1esx]] - synthetic Vpr - NMR - HIV-1 
[[5jk7]] – Vpr + DDB1 + DCAF-1 + UNG2 – X-ray solution - HIV-1 
[[1x9v]] – Dimeric structure of the Vpr C-terminal domain - NMR 
[[1vpc]] - C-terminal domain of Vpr - NMR - HIV-1 
[[1fi0]] - Vpr residues 13-33 in micelles - NMR - HIV-1 
[[1bde]] - NMR solution of Vpr peptides connected to cell cycle arrest and nuclear provirus transfer 
[[5b56]] - Importin subunit alpha-1 + Vpr C-terminal domain - crystallographic analysis 
[[1kzs]], [[1kzt]], [[1kzv]] - Vpr residues 34-51 - NMR - HIV-1 
[[1dsj]] - Vpr residues 50-75 - NMR - HIV-1 
[[1ceu]] - Vpr N-terminal domain - NMR - HIV-1 
[[1dsk]] - Vpr residues 59-86 - NMR - HIV-1 

== References ==
<references/>
[[Category:Topic Page]]

Vpr protein

2018-04-10T05:57:48Z

Elia Shlush:

<StructureSection load='1m8l' size='300' side='right' caption='NMR structure of the HIV-1 Regulatory Protein Vpr' scene=''>

== Function ==
'''Vpr protein''' (Vpr) or '''viral protein R''' is a 96 amino acid protein which encoded by the human Immunodeﬁciency virus type 1 ([[HIV-1]]). HIV-1 genome includes nine genes, six of them are accessory proteins, including ''vpr''. Vpr has several roles in the progression of acquired immunodeficiency syndrome ([https://en.wikipedia.org/wiki/AIDS AIDS]) disease, including regulation the HIV-1 pre-integration complex ([https://en.wikipedia.org/wiki/Pre-integration_complex PIC]) nuclear import and virus replication in non-dividing macrophages<ref name='Morellet2003'>PMID:12614620</ref>. Moreover, Vpr prevents mitosis of dividing infect cells by blockade at G2 phase, when the viral promoter is more active, and induced apoptosis of these cells in G1 and M phase. Both the activities of cell cycle arrest and induce apoptosis has proven to be independence by mutations that can cause only one of these affects<ref name='Gonzalez2017'>PMID:28075409</ref>.

=== Vpr induce cell cycle arrest by recruits cellular targets for degradation<ref name='Wu2016'>PMID:27571178</ref> ===
One phenotype of Vpr expression is the induction of cell cycle arrest in G2 phase. This arrest executes by engaging of damage–binding protein 1 (DDB1) and CUL4A-associated factor 1 (DCAF1) to Vpr. DCAF1 is a substrate receptor of the Cullin4–RING E3 ubiquitin ligase (CRL4) of the host ubiquitin–proteasome-mediated protein degradation pathway. Mutations in Vpr that abolish its interaction with DCAF1, or silencing of DCAF1, eliminate cell-cycle arrest. The crystal structure of <scene name='75/750237/Vpr_ddb1_dcaf1_ung2/2'>DDB1–DCAF1–HIV-1–Vpr–uracil-DNA glycosylase (UNG2) complex</scene> elucidate the molecular mechanism in which Vpr inhibits UNG2 enzymatic activity and send it for degradation:
DCAF1 WD40 domain <scene name='75/750237/Dcaf1_vpr/1'>binds to Vpr</scene> by its N-terminus and α3 helix. In addition, <scene name='75/750237/Dcaf1_ddb1/1'>DCAF1 is anchored into DDB1</scene> by a helix-loop-helix motif. These motifs are commonly found in substrate receptor proteins that bind to DDB1. Finally, Vpr uses structural mimicry to DNA to <scene name='75/750237/Vpr_ung2/1'>engages UNG2</scene>. It interacts with UNG2 by residues in the hydrophobic cleft and an insert loop (residues 266–283), which mimics the phosphate backbone in the DNA. When interacts with DNA, UNG2 Leu272 residue uses to insert into the minor groove. The importance of Leu272 residue to UNG2-Vpr interaction was demonstrated by mutagenesis. Thus, Vpr recruite the CRL4–DCAF1 E3 ubiquitin ligase and targets cellular substrates for degradation. The reason for UNG2 degradation is not clear yet. However, their is a possibility that UNG2 exerts a negative effect on HIV-1 replication.

== Disease ==
HIV-1 retrovirus is the cause of AIDS disease. HIV-1 is a RNA virus which copy its genome to the host-cell genome in infect cells. HIV-1 infects activated CD4 immune cells and macrophages. When the disease is expressing in carriers, the progressive depletion of CD4 T cells causes immunodeficiency<ref name='Emerman1996'>PMID:8805364</ref>.
For more details about AIDS disease see {{Wikipedia|AIDS}}
For details about another HIV-1 components and its replication pathway see [[HIV and accessory proteins]].

== Relevance ==
According to 2017, the currently approved anti-HIV drugs target the Pol and Env encoded proteins. These drugs are effective in reducing viral replication. Thus, because of spontaneous mutations that occur during viral replication, drug resistance is evolve<ref>PMID:28681118</ref>. Understanding of Vpr structure and molecular mechanism may facilitate the design of HIV-1 antiviral therapy by its inhibition. Deletion of both ''vpr'' and ''vpx'' genes in SIV, which their protein products in SIV combine Vpr function in HIV-1, eliminate virus replication<ref name='Emerman1996'/>. The multiple significant functions that Vpr fills in HIV-1 replication makes it an attractive candidate for antiviral therapy<ref name='Gonzalez2017'/>.

== Structural highlights<ref>PMID:12614620</ref> ==
Vpr structure is characterized by three well-defined α-helices: 17–33, 38–50 and 56–77 surrounded by flexible N and C-terminal domains. Vpr have been determined by NMR in the presence of 30% TFE several times, in [[1esx]], [[1vpc]] and [[1ceu]] structures. TFE is known to stabilize secondary structures and to prevent interactions between hydrophobic cores. However, the result was <scene name='75/750237/Vpr/1'>less globular structure</scene> than what it could be in reality. So, another NMR solution of Vpr was determined in the presence 10–30% of CD3CN, a less hydrophobic solvent, and in pure water. <scene name='75/750237/Vpr/2'>In this structure</scene> ([[1m8l]]), the structure folding around a hydrophobic core was improved, and can explain the binding properties of Vpr.

== Conservation ==
Vpr is <scene name='75/750237/Conservation/3'>highly conserved</scene> in HIV and simian immunodeficiency virus (SIV), similar retrovirus which infects non-human primates<ref name='Morellet2003'/>. In addition, all primate lentiviruses has Vpr gene whose protein product has highly conserved motifs. HIV-2 and SIVsm lentiviruses have additionally gene - Vpx. In these lentiviruses, Vpr and Vpx executes together the roles which HIV-1 Vpr perform. Vpr and Vpx has low conservation between them<ref name='Emerman1996'/>. However, Vpr and Vpx families of proteins use related structural regions to bind and recruit cellular targets to the E3 ligase complex for degradation by the proteasome<ref name='Wu2016'/>. 
[[Image:Consurf_key_small.gif|200px|right]]

</StructureSection>

== 3D Structures of Vpr protein ==

Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}

[[1m8l]] – Vpr - NMR - HIV-1 
[[1esx]] - synthetic Vpr - NMR - HIV-1 
[[5jk7]] – Vpr + DDB1 + DCAF-1 + UNG2 – X-ray solution - HIV-1 
[[1x9v]] – Dimeric structure of the Vpr C-terminal domain - NMR 
[[1vpc]] - C-terminal domain of Vpr - NMR - HIV-1 
[[1fi0]] - Vpr residues 13-33 in micelles - NMR - HIV-1 
[[1bde]] - NMR solution of Vpr peptides connected to cell cycle arrest and nuclear provirus transfer 
[[5b56]] - Importin subunit alpha-1 + Vpr C-terminal domain - crystallographic analysis 
[[1kzs]], [[1kzt]], [[1kzv]] - Vpr residues 34-51 - NMR - HIV-1 
[[1dsj]] - Vpr residues 50-75 - NMR - HIV-1 
[[1ceu]] - Vpr N-terminal domain - NMR - HIV-1 
[[1dsk]] - Vpr residues 59-86 - NMR - HIV-1 

== References ==
<references/>
[[Category:Topic Page]]

Vpr protein

2018-04-10T05:53:00Z

Elia Shlush:

<StructureSection load='1m8l' size='300' side='right' caption='NMR structure of the HIV-1 Regulatory Protein Vpr' scene=''>

== Function ==
'''Vpr protein''' (Vpr) or '''viral protein R''' is a 96 amino acid protein which encoded by the human Immunodeﬁciency virus type 1 ([[HIV-1]]). HIV-1 genome includes nine genes, six of them are accessory proteins, including ''vpr''. Vpr has several roles in the progression of acquired immunodeficiency syndrome ([https://en.wikipedia.org/wiki/AIDS AIDS]) disease, including regulation the HIV-1 pre-integration complex ([https://en.wikipedia.org/wiki/Pre-integration_complex PIC]) nuclear import and virus replication in non-dividing macrophages<ref name='Morellet2003'>PMID:12614620</ref>. Moreover, Vpr prevents mitosis of dividing infect cells by blockade at G2 phase, when the viral promoter is more active, and induced apoptosis of these cells in G1 and M phase. Both the activities of cell cycle arrest and induce apoptosis has proven to be independence by mutations that can cause only one of these affects<ref name='Gonzalez2017'>PMID:28075409</ref>.

=== Vpr induce cell cycle arrest by recruits cellular targets for degradation<ref name='Wu2016'>PMID:27571178</ref> ===
One phenotype of Vpr expression is the induction of cell cycle arrest in G2 phase. This arrest executes by engaging of damage–binding protein 1 (DDB1) and CUL4A-associated factor 1 (DCAF1) to Vpr. DCAF1 is a substrate receptor of the Cullin4–RING E3 ubiquitin ligase (CRL4) of the host ubiquitin–proteasome-mediated protein degradation pathway. Mutations in Vpr that abolish its interaction with DCAF1, or silencing of DCAF1, eliminate cell-cycle arrest. The crystal structure of <scene name='75/750237/Vpr_ddb1_dcaf1_ung2/2'>DDB1–DCAF1–HIV-1–Vpr–uracil-DNA glycosylase (UNG2) complex</scene> elucidate the molecular mechanism in which Vpr inhibits UNG2 enzymatic activity and send it for degradation:
DCAF1 WD40 domain <scene name='75/750237/Dcaf1_vpr/1'>binds to Vpr</scene> by its N-terminus and α3 helix. In addition, <scene name='75/750237/Dcaf1_ddb1/1'>DCAF1 is anchored into DDB1</scene> by a helix-loop-helix motif. These motifs are commonly found in substrate receptor proteins that bind to DDB1. Finally, Vpr uses structural mimicry to DNA to <scene name='75/750237/Vpr_ung2/1'>engages UNG2</scene>. It interacts with UNG2 by residues in the hydrophobic cleft and an insert loop (residues 266–283), which mimics the phosphate backbone in the DNA. When interacts with DNA, UNG2 Leu272 residue uses to insert into the minor groove. The importance of Leu272 residue to UNG2-Vpr interaction was demonstrated by mutagenesis. Thus, Vpr recruite the CRL4–DCAF1 E3 ubiquitin ligase and targets cellular substrates for degradation. The reason for UNG2 degradation is not clear yet. However, their is a possibility that UNG2 exerts a negative effect on HIV-1 replication.

== Disease ==
HIV-1 retrovirus is the cause of AIDS disease. HIV-1 is a RNA virus which copy its genome to the host-cell genome in infect cells. HIV-1 infects activated CD4 immune cells and macrophages. When the disease is expressing in carriers, the progressive depletion of CD4 T cells causes immunodeficiency<ref name='Emerman1996'>PMID:8805364</ref>.
For more details about AIDS disease see {{Wikipedia|AIDS}}
For details about another HIV-1 components and its replication pathway see [[HIV and accessory proteins]].

== Relevance ==
According to 2017, the currently approved anti-HIV drugs target the Pol and Env encoded proteins. These drugs are effective in reducing viral replication. Thus, because of spontaneous mutations that occur during viral replication, drug resistance is evolve<ref>PMID:28681118</ref>. Understanding of Vpr structure and molecular mechanism may facilitate the design of HIV-1 antiviral therapy by its inhibition. Deletion of both ''vpr'' and ''vpx'' genes in SIV, which their protein products in SIV combine Vpr function in HIV-1, eliminate virus replication<ref name='Emerman1996'/>. The multiple significant functions that Vpr fills in HIV-1 replication makes it an attractive candidate for antiviral therapy<ref name='Gonzalez2017'/>.

== Structural highlights<ref>PMID:12614620</ref> ==
Vpr structure is characterized by three well-defined α-helices: 17–33, 38–50 and 56–77 surrounded by flexible N and C-terminal domains. Vpr have been determined by NMR in the presence of 30% TFE several times, in [[1esx]], [[1vpc]] and [[1ceu]] structures. TFE is known to stabilize secondary structures and to prevent interactions between hydrophobic cores. However, the result was <scene name='75/750237/Vpr/1'>less globular structure</scene> than what it could be in reality. So, another NMR solution of Vpr is determined in the presence 10–30% of CD3CN, a less hydrophobic solvent, and in pure water. <scene name='75/750237/Vpr/2'>In this structure</scene> ([[1m8l]]), the structure folding around a hydrophobic core was improved, and can explain the binding properties of Vpr.

== Conservation ==
Vpr is <scene name='75/750237/Conservation/3'>highly conserved</scene> in HIV and simian immunodeficiency virus (SIV), similar retrovirus which infects non-human primates<ref name='Morellet2003'/>. In addition, all primate lentiviruses has Vpr gene whose protein product has highly conserved motifs. HIV-2 and SIVsm lentiviruses have additionally gene - Vpx. In these lentiviruses, Vpr and Vpx executes together the roles which HIV-1 Vpr perform. Vpr and Vpx has low conservation between them<ref name='Emerman1996'/>. However, Vpr and Vpx families of proteins use related structural regions to bind and recruit cellular targets to the E3 ligase complex for degradation by the proteasome<ref name='Wu2016'/>. 
[[Image:Consurf_key_small.gif|200px|right]]

</StructureSection>

== 3D Structures of Vpr protein ==

Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}

[[1m8l]] – Vpr - NMR - HIV-1 
[[1esx]] - synthetic Vpr - NMR - HIV-1 
[[5jk7]] – Vpr + DDB1 + DCAF-1 + UNG2 – X-ray solution - HIV-1 
[[1x9v]] – Dimeric structure of the Vpr C-terminal domain - NMR 
[[1vpc]] - C-terminal domain of Vpr - NMR - HIV-1 
[[1fi0]] - Vpr residues 13-33 in micelles - NMR - HIV-1 
[[1bde]] - NMR solution of Vpr peptides connected to cell cycle arrest and nuclear provirus transfer 
[[5b56]] - Importin subunit alpha-1 + Vpr C-terminal domain - crystallographic analysis 
[[1kzs]], [[1kzt]], [[1kzv]] - Vpr residues 34-51 - NMR - HIV-1 
[[1dsj]] - Vpr residues 50-75 - NMR - HIV-1 
[[1ceu]] - Vpr N-terminal domain - NMR - HIV-1 
[[1dsk]] - Vpr residues 59-86 - NMR - HIV-1 

== References ==
<references/>
[[Category:Topic Page]]

Vpr protein

2018-04-10T05:48:46Z

Elia Shlush:

<StructureSection load='1m8l' size='300' side='right' caption='NMR structure of the HIV-1 Regulatory Protein Vpr' scene=''>

== Function ==
'''Vpr protein''' (Vpr) or '''viral protein R''' is a 96 amino acid protein which encoded by the human Immunodeﬁciency virus type 1 ([[HIV-1]]). HIV-1 genome includes nine genes, six of them are accessory proteins, including ''vpr''. Vpr has several roles in the progression of acquired immunodeficiency syndrome ([https://en.wikipedia.org/wiki/AIDS AIDS]) disease, including regulation the HIV-1 pre-integration complex ([https://en.wikipedia.org/wiki/Pre-integration_complex PIC]) nuclear import and virus replication in non-dividing macrophages<ref name='Morellet2003'>PMID:12614620</ref>. Moreover, Vpr prevents mitosis of dividing infect cells by blockade at G2 phase, when the viral promoter is more active, and induced apoptosis of these cells in G1 and M phase. Both the activities of cell cycle arrest and induce apoptosis has proven to be independence by mutations that can cause only one of these affects<ref name='Gonzalez2017'>PMID:28075409</ref>.

=== Vpr induce cell cycle arrest by recruits cellular targets for degradation<ref name='Wu2016'>PMID:27571178</ref> ===
One phenotype of Vpr expression is the induction of cell cycle arrest in G2 phase. This arrest executes by engaging of damage–binding protein 1 (DDB1) and CUL4A-associated factor 1 (DCAF1) to Vpr. DCAF1 is a substrate receptor of the Cullin4–RING E3 ubiquitin ligase (CRL4) of the host ubiquitin–proteasome-mediated protein degradation pathway. Mutations in Vpr that abolish its interaction with DCAF1, or silencing of DCAF1, eliminate cell-cycle arrest. The crystal structure of <scene name='75/750237/Vpr_ddb1_dcaf1_ung2/2'>DDB1–DCAF1–HIV-1–Vpr–uracil-DNA glycosylase (UNG2) complex</scene> elucidate the molecular mechanism in which Vpr inhibits UNG2 enzymatic activity and send it for degradation:
DCAF1 WD40 domain <scene name='75/750237/Dcaf1_vpr/1'>binds to Vpr</scene> by its N-terminus and α3 helix. In addition, <scene name='75/750237/Dcaf1_ddb1/1'>DCAF1 is anchored into DDB1</scene> by a helix-loop-helix motif. These motifs are commonly found in substrate receptor proteins that bind to DDB1. Finally, Vpr uses structural mimicry to DNA to <scene name='75/750237/Vpr_ung2/1'>engages UNG2</scene>. It interacts with UNG2 by residues in the hydrophobic cleft and an insert loop (residues 266–283), which mimics the phosphate backbone in the DNA. When interacts with DNA, UNG2 Leu272 residue uses to insert into the minor groove. The importance of Leu272 residue to UNG2-Vpr interaction was demonstrated by mutagenesis. Thus, Vpr recruite the CRL4–DCAF1 E3 ubiquitin ligase and targets cellular substrates for degradation. The reason for UNG2 degradation is not clear yet. However, their is a possibility that UNG2 exerts a negative effect on HIV-1 replication.

== Disease ==
HIV-1 retrovirus is the cause of AIDS disease. HIV-1 is a RNA virus which copy its genome to the host-cell genome in infect cells. HIV-1 infects activated CD4 immune cells and macrophages. When the disease is expressing in carriers, the progressive depletion of CD4 T cells causes immunodeficiency<ref name='Emerman1996'>PMID:8805364</ref>.
For more details about AIDS disease see {{Wikipedia|AIDS}}
For details about another HIV-1 components and its replication pathway see [[HIV and accessory proteins]].

== Relevance ==
According to 2017, the currently approved anti-HIV drugs target the Pol and Env encoded proteins. These drugs are effective in reducing viral replication. Thus, because of spontaneous mutations that occur during viral replication, drug resistance is evolve<ref>PMID:28681118</ref>. Understanding of Vpr structure and molecular mechanism may facilitate the design of HIV-1 antiviral therapy by its inhibition. Deletion of both ''vpr'' and ''vpx'' genes in SIV, which their protein products in SIV combine Vpr function in HIV-1, eliminate virus replication<ref name='Emerman1996'/>. The multiple significant functions that Vpr fills in HIV-1 replication makes it an attractive candidate for antiviral therapy<ref name='Gonzalez2017'/>.

== Structural highlights<ref>PMID:12614620</ref> ==
Vpr structure is characterized by three well-defined α-helices: 17–33, 38–50 and 56–77 surrounded by flexible N and C-terminal domains. Vpr have been determined by NMR in the presence of 30% TFE several times, in [[1esx]], [[1vpc]] and [[1ceu]] structures. TFE is known to stabilize secondary structures and to prevent interactions between hydrophobic cores. However, the result was <scene name='75/750237/Vpr/1'>less globular structure</scene> than what it could be in reality. So, another NMR solution of Vpr is determined in the presence 10–30% of CD3CN, a less hydrophobic solvent, and in pure water. In this structure ([[1m8l]]), the structure folding around a hydrophobic core was improved, and can explain the binding properties of Vpr.

== Conservation ==
Vpr is <scene name='75/750237/Conservation/3'>highly conserved</scene> in HIV and simian immunodeficiency virus (SIV), similar retrovirus which infects non-human primates<ref name='Morellet2003'/>. In addition, all primate lentiviruses has Vpr gene whose protein product has highly conserved motifs. HIV-2 and SIVsm lentiviruses have additionally gene - Vpx. In these lentiviruses, Vpr and Vpx executes together the roles which HIV-1 Vpr perform. Vpr and Vpx has low conservation between them<ref name='Emerman1996'/>. However, Vpr and Vpx families of proteins use related structural regions to bind and recruit cellular targets to the E3 ligase complex for degradation by the proteasome<ref name='Wu2016'/>. 
[[Image:Consurf_key_small.gif|200px|right]]

</StructureSection>

== 3D Structures of Vpr protein ==

Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}

[[1m8l]] – Vpr - NMR - HIV-1 
[[1esx]] - synthetic Vpr - NMR - HIV-1 
[[5jk7]] – Vpr + DDB1 + DCAF-1 + UNG2 – X-ray solution - HIV-1 
[[1x9v]] – Dimeric structure of the Vpr C-terminal domain - NMR 
[[1vpc]] - C-terminal domain of Vpr - NMR - HIV-1 
[[1fi0]] - Vpr residues 13-33 in micelles - NMR - HIV-1 
[[1bde]] - NMR solution of Vpr peptides connected to cell cycle arrest and nuclear provirus transfer 
[[5b56]] - Importin subunit alpha-1 + Vpr C-terminal domain - crystallographic analysis 
[[1kzs]], [[1kzt]], [[1kzv]] - Vpr residues 34-51 - NMR - HIV-1 
[[1dsj]] - Vpr residues 50-75 - NMR - HIV-1 
[[1ceu]] - Vpr N-terminal domain - NMR - HIV-1 
[[1dsk]] - Vpr residues 59-86 - NMR - HIV-1 

== References ==
<references/>
[[Category:Topic Page]]

Vpr protein

2018-04-10T05:40:07Z

Elia Shlush:

<StructureSection load='1m8l' size='300' side='right' caption='NMR structure of the HIV-1 Regulatory Protein Vpr' scene=''>

== Function ==
'''Vpr protein''' (Vpr) or '''viral protein R''' is a 96 amino acid protein which encoded by the human Immunodeﬁciency virus type 1 ([[HIV-1]]). HIV-1 genome includes nine genes, six of them are accessory proteins, including ''vpr''. Vpr has several roles in the progression of acquired immunodeficiency syndrome ([https://en.wikipedia.org/wiki/AIDS AIDS]) disease, including regulation the HIV-1 pre-integration complex ([https://en.wikipedia.org/wiki/Pre-integration_complex PIC]) nuclear import and virus replication in non-dividing macrophages<ref name='Morellet2003'>PMID:12614620</ref>. Moreover, Vpr prevents mitosis of dividing infect cells by blockade at G2 phase, when the viral promoter is more active, and induced apoptosis of these cells in G1 and M phase. Both the activities of cell cycle arrest and induce apoptosis has proven to be independence by mutations that can cause only one of these affects<ref name='Gonzalez2017'>PMID:28075409</ref>.

=== Vpr induce cell cycle arrest by recruits cellular targets for degradation<ref name='Wu2016'>PMID:27571178</ref> ===
One phenotype of Vpr expression is the induction of cell cycle arrest in G2 phase. This arrest executes by engaging of damage–binding protein 1 (DDB1) and CUL4A-associated factor 1 (DCAF1) to Vpr. DCAF1 is a substrate receptor of the Cullin4–RING E3 ubiquitin ligase (CRL4) of the host ubiquitin–proteasome-mediated protein degradation pathway. Mutations in Vpr that abolish its interaction with DCAF1, or silencing of DCAF1, eliminate cell-cycle arrest. The crystal structure of <scene name='75/750237/Vpr_ddb1_dcaf1_ung2/2'>DDB1–DCAF1–HIV-1–Vpr–uracil-DNA glycosylase (UNG2) complex</scene> elucidate the molecular mechanism in which Vpr inhibits UNG2 enzymatic activity and send it for degradation:
DCAF1 WD40 domain <scene name='75/750237/Dcaf1_vpr/1'>binds to Vpr</scene> by its N-terminus and α3 helix. In addition, <scene name='75/750237/Dcaf1_ddb1/1'>DCAF1 is anchored into DDB1</scene> by a helix-loop-helix motif. These motifs are commonly found in substrate receptor proteins that bind to DDB1. Finally, Vpr uses structural mimicry to DNA to <scene name='75/750237/Vpr_ung2/1'>engages UNG2</scene>. It interacts with UNG2 by residues in the hydrophobic cleft and an insert loop (residues 266–283), which mimics the phosphate backbone in the DNA. When interacts with DNA, UNG2 Leu272 residue uses to insert into the minor groove. The importance of Leu272 residue to UNG2-Vpr interaction was demonstrated by mutagenesis. Thus, Vpr recruite the CRL4–DCAF1 E3 ubiquitin ligase and targets cellular substrates for degradation. The reason for UNG2 degradation is not clear yet. However, their is a possibility that UNG2 exerts a negative effect on HIV-1 replication.

== Disease ==
HIV-1 retrovirus is the cause of AIDS disease. HIV-1 is a RNA virus which copy its genome to the host-cell genome in infect cells. HIV-1 infects activated CD4 immune cells and macrophages. When the disease is expressing in carriers, the progressive depletion of CD4 T cells causes immunodeficiency<ref name='Emerman1996'>PMID:8805364</ref>.
For more details about AIDS disease see {{Wikipedia|AIDS}}
For details about another HIV-1 components and its replication pathway see [[HIV and accessory proteins]].

== Relevance ==
According to 2017, the currently approved anti-HIV drugs target the Pol and Env encoded proteins. These drugs are effective in reducing viral replication. Thus, because of spontaneous mutations that occur during viral replication, drug resistance is evolve<ref>PMID:28681118</ref>. Understanding of Vpr structure and molecular mechanism may facilitate the design of HIV-1 antiviral therapy by its inhibition. Deletion of both ''vpr'' and ''vpx'' genes in SIV, which their protein products in SIV combine Vpr function in HIV-1, eliminate virus replication<ref name='Emerman1996'/>. The multiple significant functions that Vpr fills in HIV-1 replication makes it an attractive candidate for antiviral therapy<ref name='Gonzalez2017'/>.

== Structural highlights<ref>PMID:12614620</ref> ==
Vpr structure is characterized by three well-defined α-helices: 17–33, 38–50 and 56–77 surrounded by flexible N and C-terminal domains. Vpr have been determined by NMR in the presence of 30% TFE several times, in [[1esx]], [[1vpc]] and [[1ceu]] structures. TFE is known to stabilize secondary structures and to prevent interactions between hydrophobic cores. However, the result was less globular structure than what it could be in reality. So, another NMR solution of Vpr is determined in the presence 10–30% of CD3CN, a less hydrophobic solvent, and in pure water. In this structure ([[1m8l]]), the structure folding around a hydrophobic core was improved, and can explain the binding properties of Vpr.

== Conservation ==
Vpr is <scene name='75/750237/Conservation/3'>highly conserved</scene> in HIV and simian immunodeficiency virus (SIV), similar retrovirus which infects non-human primates<ref name='Morellet2003'/>. In addition, all primate lentiviruses has Vpr gene whose protein product has highly conserved motifs. HIV-2 and SIVsm lentiviruses have additionally gene - Vpx. In these lentiviruses, Vpr and Vpx executes together the roles which HIV-1 Vpr perform. Vpr and Vpx has low conservation between them<ref name='Emerman1996'/>. However, Vpr and Vpx families of proteins use related structural regions to bind and recruit cellular targets to the E3 ligase complex for degradation by the proteasome<ref name='Wu2016'/>. 
[[Image:Consurf_key_small.gif|200px|right]]

</StructureSection>

== 3D Structures of Vpr protein ==

Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}

[[1m8l]] – Vpr - NMR - HIV-1 
[[1esx]] - synthetic Vpr - NMR - HIV-1 
[[5jk7]] – Vpr + DDB1 + DCAF-1 + UNG2 – X-ray solution - HIV-1 
[[1x9v]] – Dimeric structure of the Vpr C-terminal domain - NMR 
[[1vpc]] - C-terminal domain of Vpr - NMR - HIV-1 
[[1fi0]] - Vpr residues 13-33 in micelles - NMR - HIV-1 
[[1bde]] - NMR solution of Vpr peptides connected to cell cycle arrest and nuclear provirus transfer 
[[5b56]] - Importin subunit alpha-1 + Vpr C-terminal domain - crystallographic analysis 
[[1kzs]], [[1kzt]], [[1kzv]] - Vpr residues 34-51 - NMR - HIV-1 
[[1dsj]] - Vpr residues 50-75 - NMR - HIV-1 
[[1ceu]] - Vpr N-terminal domain - NMR - HIV-1 
[[1dsk]] - Vpr residues 59-86 - NMR - HIV-1 

== References ==
<references/>
[[Category:Topic Page]]

Vpr protein

2018-04-09T16:01:25Z

Elia Shlush:

<StructureSection load='1m8l' size='300' side='right' caption='NMR structure of the HIV-1 Regulatory Protein Vpr' scene=''>

== Function ==
'''Vpr protein''' (Vpr) or '''viral protein R''' is a 96 amino acid protein which encoded by the human Immunodeﬁciency virus type 1 ([[HIV-1]]). HIV-1 genome includes nine genes, six of them are accessory proteins, including ''vpr''. Vpr has several roles in the progression of acquired immunodeficiency syndrome ([https://en.wikipedia.org/wiki/AIDS AIDS]) disease, including regulation the HIV-1 pre-integration complex ([https://en.wikipedia.org/wiki/Pre-integration_complex PIC]) nuclear import and virus replication in non-dividing macrophages<ref name='Morellet2003'>PMID:12614620</ref>. Moreover, Vpr prevents mitosis of dividing infect cells by blockade at G2 phase, when the viral promoter is more active, and induced apoptosis of these cells in G1 and M phase. Both the activities of cell cycle arrest and induce apoptosis has proven to be independence by mutations that can cause only one of these affects<ref name='Gonzalez2017'>PMID:28075409</ref>.

=== Vpr induce cell cycle arrest by recruits cellular targets for degradation<ref name='Wu2016'>PMID:27571178</ref> ===
One phenotype of Vpr expression is the induction of cell cycle arrest in G2 phase. This arrest executes by engaging of damage–binding protein 1 (DDB1) and CUL4A-associated factor 1 (DCAF1) to Vpr. DCAF1 is a substrate receptor of the Cullin4–RING E3 ubiquitin ligase (CRL4) of the host ubiquitin–proteasome-mediated protein degradation pathway. Mutations in Vpr that abolish its interaction with DCAF1, or silencing of DCAF1, eliminate cell-cycle arrest. The crystal structure of <scene name='75/750237/Vpr_ddb1_dcaf1_ung2/2'>DDB1–DCAF1–HIV-1–Vpr–uracil-DNA glycosylase (UNG2) complex</scene> elucidate the molecular mechanism in which Vpr inhibits UNG2 enzymatic activity and send it for degradation:
DCAF1 WD40 domain <scene name='75/750237/Dcaf1_vpr/1'>binds to Vpr</scene> by its N-terminus and α3 helix. In addition, <scene name='75/750237/Dcaf1_ddb1/1'>DCAF1 is anchored into DDB1</scene> by a helix-loop-helix motif. These motifs are commonly found in substrate receptor proteins that bind to DDB1. Finally, Vpr uses structural mimicry to DNA to <scene name='75/750237/Vpr_ung2/1'>engages UNG2</scene>. It interacts with UNG2 by residues in the hydrophobic cleft and an insert loop (residues 266–283), which mimics the phosphate backbone in the DNA. When interacts with DNA, UNG2 Leu272 residue uses to insert into the minor groove. The importance of Leu272 residue to UNG2-Vpr interaction was demonstrated by mutagenesis. Thus, Vpr recruite the CRL4–DCAF1 E3 ubiquitin ligase and targets cellular substrates for degradation. The reason for UNG2 degradation is not clear yet. However, their is a possibility that UNG2 exerts a negative effect on HIV-1 replication.

== Disease ==
HIV-1 retrovirus is the cause of AIDS disease. HIV-1 is a RNA virus which copy its genome to the host-cell genome in infect cells. HIV-1 infects activated CD4 immune cells and macrophages. When the disease is expressing in carriers, the progressive depletion of CD4 T cells causes immunodeficiency<ref name='Emerman1996'>PMID:8805364</ref>.
For more details about AIDS disease see {{Wikipedia|AIDS}}
For details about another HIV-1 components and its replication pathway see [[HIV and accessory proteins]].

== Relevance ==
According to 2017, the currently approved anti-HIV drugs target the Pol and Env encoded proteins. These drugs are effective in reducing viral replication. Thus, because of spontaneous mutations that occur during viral replication, drug resistance is evolve<ref>PMID:28681118</ref>. Understanding of Vpr structure and molecular mechanism may facilitate the design of HIV-1 antiviral therapy by its inhibition. Deletion of both ''vpr'' and ''vpx'' genes in SIV, which their protein products in SIV combine Vpr function in HIV-1, eliminate virus replication<ref name='Emerman1996'/>. The multiple significant functions that Vpr fills in HIV-1 replication makes it an attractive candidate for antiviral therapy<ref name='Gonzalez2017'/>.

== Conservation ==
Vpr is <scene name='75/750237/Conservation/3'>highly conserved</scene> in HIV and simian immunodeficiency virus (SIV), similar retrovirus which infects non-human primates<ref name='Morellet2003'/>. In addition, all primate lentiviruses has Vpr gene whose protein product has highly conserved motifs. HIV-2 and SIVsm lentiviruses have additionally gene - Vpx. In these lentiviruses, Vpr and Vpx executes together the roles which HIV-1 Vpr perform. Vpr and Vpx has low conservation between them<ref name='Emerman1996'/>. However, Vpr and Vpx families of proteins use related structural regions to bind and recruit cellular targets to the E3 ligase complex for degradation by the proteasome<ref name='Wu2016'/>. 
[[Image:Consurf_key_small.gif|200px|right]]

</StructureSection>

== 3D Structures of Vpr protein ==

Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}

[[1m8l]] – Vpr - NMR - HIV-1 
[[1esx]] - synthetic Vpr - NMR - HIV-1 
[[5jk7]] – Vpr + DDB1 + DCAF-1 + UNG2 – X-ray solution - HIV-1 
[[1x9v]] – Dimeric structure of the Vpr C-terminal domain - NMR 
[[1vpc]] - C-terminal domain of Vpr - NMR - HIV-1 
[[1fi0]] - Vpr residues 13-33 in micelles - NMR - HIV-1 
[[1bde]] - NMR solution of Vpr peptides connected to cell cycle arrest and nuclear provirus transfer 
[[5b56]] - Importin subunit alpha-1 + Vpr C-terminal domain - crystallographic analysis 
[[1kzs]], [[1kzt]], [[1kzv]] - Vpr residues 34-51 - NMR - HIV-1 
[[1dsj]] - Vpr residues 50-75 - NMR - HIV-1 
[[1ceu]] - Vpr N-terminal domain - NMR - HIV-1 
[[1dsk]] - Vpr residues 59-86 - NMR - HIV-1 

== References ==
<references/>
[[Category:Topic Page]]

Vpr protein

2018-04-09T15:48:45Z

Elia Shlush:

<StructureSection load='1m8l' size='300' side='right' caption='NMR structure of the HIV-1 Regulatory Protein Vpr' scene=''>

== Function ==
'''Vpr protein''' (Vpr) or '''viral protein R''' is a 96 amino acid protein which encoded by the human Immunodeﬁciency virus type 1 ([[HIV-1]]). HIV-1 genome includes nine genes, six of them are accessory proteins, including ''vpr''. Vpr has several roles in the progression of acquired immunodeficiency syndrome ([https://en.wikipedia.org/wiki/AIDS AIDS]) disease, including regulation the HIV-1 pre-integration complex ([https://en.wikipedia.org/wiki/Pre-integration_complex PIC]) nuclear import and virus replication in non-dividing macrophages<ref name='Morellet2003'>PMID:12614620</ref>. Moreover, Vpr prevents mitosis of dividing infect cells by blockade at G2 phase, when the viral promoter is more active, and induced apoptosis of these cells in G1 and M phase. Both the activities of cell cycle arrest and induce apoptosis has proven to be independence by mutations that can cause only one of these affects<ref name='Gonzalez2017'>PMID:28075409</ref>.

=== Vpr induce cell cycle arrest by recruits cellular targets for degradation<ref name='Wu2016'>PMID:27571178</ref> ===
One phenotype of Vpr expression is the induction of cell cycle arrest in G2 phase. This arrest executes by engaging of damage–binding protein 1 (DDB1) and CUL4A-associated factor 1 (DCAF1) to Vpr. DCAF1 is a substrate receptor of the Cullin4–RING E3 ubiquitin ligase (CRL4) of the host ubiquitin–proteasome-mediated protein degradation pathway. Mutations in Vpr that abolish its interaction with DCAF1, or silencing of DCAF1, eliminate cell-cycle arrest. The crystal structure of <scene name='75/750237/Vpr_ddb1_dcaf1_ung2/2'>DDB1–DCAF1–HIV-1–Vpr–uracil-DNA glycosylase (UNG2) complex</scene> elucidate the molecular mechanism in which Vpr inhibits UNG2 enzymatic activity and send it for degradation:
DCAF1 WD40 domain <scene name='75/750237/Dcaf1_vpr/1'>binds to Vpr</scene> by its N-terminus and α3 helix. In addition, DCAF1 is anchored into DDB1 by a helix-loop-helix motif. These motifs are commonly found in substrate receptor proteins that bind to DDB1. Finally, Vpr uses structural mimicry to DNA to <scene name='75/750237/Vpr_ung2/1'>engages UNG2</scene>. It interacts with UNG2 by residues in the hydrophobic cleft and an insert loop (residues 266–283), which mimics the phosphate backbone in the DNA. When interacts with DNA, UNG2 Leu272 residue uses to insert into the minor groove. The importance of Leu272 residue to UNG2-Vpr interaction was demonstrated by mutagenesis. Thus, Vpr recruite the CRL4–DCAF1 E3 ubiquitin ligase and targets cellular substrates for degradation. The reason for UNG2 degradation is not clear yet. However, their is a possibility that UNG2 exerts a negative effect on HIV-1 replication.

== Disease ==
HIV-1 retrovirus is the cause of AIDS disease. HIV-1 is a RNA virus which copy its genome to the host-cell genome in infect cells. HIV-1 infects activated CD4 immune cells and macrophages. When the disease is expressing in carriers, the progressive depletion of CD4 T cells causes immunodeficiency<ref name='Emerman1996'>PMID:8805364</ref>.
For more details about AIDS disease see {{Wikipedia|AIDS}}
For details about another HIV-1 components and its replication pathway see [[HIV and accessory proteins]].

== Relevance ==
According to 2017, the currently approved anti-HIV drugs target the Pol and Env encoded proteins. These drugs are effective in reducing viral replication. Thus, because of spontaneous mutations that occur during viral replication, drug resistance is evolve<ref>PMID:28681118</ref>. Understanding of Vpr structure and molecular mechanism may facilitate the design of HIV-1 antiviral therapy by its inhibition. Deletion of both ''vpr'' and ''vpx'' genes in SIV, which their protein products in SIV combine Vpr function in HIV-1, eliminate virus replication<ref name='Emerman1996'/>. The multiple significant functions that Vpr fills in HIV-1 replication makes it an attractive candidate for antiviral therapy<ref name='Gonzalez2017'/>.

== Conservation ==
Vpr is <scene name='75/750237/Conservation/3'>highly conserved</scene> in HIV and simian immunodeficiency virus (SIV), similar retrovirus which infects non-human primates<ref name='Morellet2003'/>. In addition, all primate lentiviruses has Vpr gene whose protein product has highly conserved motifs. HIV-2 and SIVsm lentiviruses have additionally gene - Vpx. In these lentiviruses, Vpr and Vpx executes together the roles which HIV-1 Vpr perform. Vpr and Vpx has low conservation between them<ref name='Emerman1996'/>. However, Vpr and Vpx families of proteins use related structural regions to bind and recruit cellular targets to the E3 ligase complex for degradation by the proteasome<ref name='Wu2016'/>. 
[[Image:Consurf_key_small.gif|200px|right]]

</StructureSection>

== 3D Structures of Vpr protein ==

Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}

[[1m8l]] – Vpr - NMR - HIV-1 
[[1esx]] - synthetic Vpr - NMR - HIV-1 
[[5jk7]] – Vpr + DDB1 + DCAF-1 + UNG2 – X-ray solution - HIV-1 
[[1x9v]] – Dimeric structure of the Vpr C-terminal domain - NMR 
[[1vpc]] - C-terminal domain of Vpr - NMR - HIV-1 
[[1fi0]] - Vpr residues 13-33 in micelles - NMR - HIV-1 
[[1bde]] - NMR solution of Vpr peptides connected to cell cycle arrest and nuclear provirus transfer 
[[5b56]] - Importin subunit alpha-1 + Vpr C-terminal domain - crystallographic analysis 
[[1kzs]], [[1kzt]], [[1kzv]] - Vpr residues 34-51 - NMR - HIV-1 
[[1dsj]] - Vpr residues 50-75 - NMR - HIV-1 
[[1ceu]] - Vpr N-terminal domain - NMR - HIV-1 
[[1dsk]] - Vpr residues 59-86 - NMR - HIV-1 

== References ==
<references/>
[[Category:Topic Page]]

Vpr protein

2018-04-09T15:37:51Z

Elia Shlush:

<StructureSection load='1m8l' size='300' side='right' caption='NMR structure of the HIV-1 Regulatory Protein Vpr' scene=''>

== Function ==
'''Vpr protein''' (Vpr) or '''viral protein R''' is a 96 amino acid protein which encoded by the human Immunodeﬁciency virus type 1 ([[HIV-1]]). HIV-1 genome includes nine genes, six of them are accessory proteins, including ''vpr''. Vpr has several roles in the progression of acquired immunodeficiency syndrome ([https://en.wikipedia.org/wiki/AIDS AIDS]) disease, including regulation the HIV-1 pre-integration complex ([https://en.wikipedia.org/wiki/Pre-integration_complex PIC]) nuclear import and virus replication in non-dividing macrophages<ref name='Morellet2003'>PMID:12614620</ref>. Moreover, Vpr prevents mitosis of dividing infect cells by blockade at G2 phase, when the viral promoter is more active, and induced apoptosis of these cells in G1 and M phase. Both the activities of cell cycle arrest and induce apoptosis has proven to be independence by mutations that can cause only one of these affects<ref name='Gonzalez2017'>PMID:28075409</ref>.

=== Vpr induce cell cycle arrest by recruits cellular targets for degradation<ref name='Wu2016'>PMID:27571178</ref> ===
One phenotype of Vpr expression is the induction of cell cycle arrest in G2 phase. This arrest executes by engaging of damage–binding protein 1 (DDB1) and CUL4A-associated factor 1 (DCAF1) to Vpr. DCAF1 is a substrate receptor of the Cullin4–RING E3 ubiquitin ligase (CRL4) of the host ubiquitin–proteasome-mediated protein degradation pathway. Mutations in Vpr that abolish its interaction with DCAF1, or silencing of DCAF1, eliminate cell-cycle arrest. The crystal structure of <scene name='75/750237/Vpr_ddb1_dcaf1_ung2/2'>DDB1–DCAF1–HIV-1–Vpr–uracil-DNA glycosylase (UNG2) complex</scene> elucidate the molecular mechanism in which Vpr inhibits UNG2 enzymatic activity and send it for degradation:
DCAF1 WD40 domain <scene name='75/750237/Dcaf1_vpr/1'>binds to Vpr</scene> by its N-terminus and α3 helix. In addition, DCAF1 is anchored into DDB1 by a helix-loop-helix motif. These motifs are commonly found in substrate receptor proteins that bind to DDB1. Finally, Vpr uses structural mimicry to DNA to <scene name='75/750237/Dcaf1_ung2/1'>engages UNG2</scene>. It interacts with UNG2 by residues in the hydrophobic cleft and an insert loop (residues 266–283), which mimics the phosphate backbone in the DNA. When interacts with DNA, UNG2 Leu272 residue uses to insert into the minor groove. The importance of Leu272 residue to UNG2-Vpr interaction was demonstrated by mutagenesis. Thus, Vpr recruite the CRL4–DCAF1 E3 ubiquitin ligase and targets cellular substrates for degradation. The reason for UNG2 degradation is not clear yet. However, their is a possibility that UNG2 exerts a negative effect on HIV-1 replication.

== Disease ==
HIV-1 retrovirus is the cause of AIDS disease. HIV-1 is a RNA virus which copy its genome to the host-cell genome in infect cells. HIV-1 infects activated CD4 immune cells and macrophages. When the disease is expressing in carriers, the progressive depletion of CD4 T cells causes immunodeficiency<ref name='Emerman1996'>PMID:8805364</ref>.
For more details about AIDS disease see {{Wikipedia|AIDS}}
For details about another HIV-1 components and its replication pathway see [[HIV and accessory proteins]].

== Relevance ==
According to 2017, the currently approved anti-HIV drugs target the Pol and Env encoded proteins. These drugs are effective in reducing viral replication. Thus, because of spontaneous mutations that occur during viral replication, drug resistance is evolve<ref>PMID:28681118</ref>. Understanding of Vpr structure and molecular mechanism may facilitate the design of HIV-1 antiviral therapy by its inhibition. Deletion of both ''vpr'' and ''vpx'' genes in SIV, which their protein products in SIV combine Vpr function in HIV-1, eliminate virus replication<ref name='Emerman1996'/>. The multiple significant functions that Vpr fills in HIV-1 replication makes it an attractive candidate for antiviral therapy<ref name='Gonzalez2017'/>.

== Conservation ==
Vpr is <scene name='75/750237/Conservation/3'>highly conserved</scene> in HIV and simian immunodeficiency virus (SIV), similar retrovirus which infects non-human primates<ref name='Morellet2003'/>. In addition, all primate lentiviruses has Vpr gene whose protein product has highly conserved motifs. HIV-2 and SIVsm lentiviruses have additionally gene - Vpx. In these lentiviruses, Vpr and Vpx executes together the roles which HIV-1 Vpr perform. Vpr and Vpx has low conservation between them<ref name='Emerman1996'/>. However, Vpr and Vpx families of proteins use related structural regions to bind and recruit cellular targets to the E3 ligase complex for degradation by the proteasome<ref name='Wu2016'/>. 
[[Image:Consurf_key_small.gif|200px|right]]

</StructureSection>

== 3D Structures of Vpr protein ==

Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}

[[1m8l]] – Vpr - NMR - HIV-1 
[[1esx]] - synthetic Vpr - NMR - HIV-1 
[[5jk7]] – Vpr + DDB1 + DCAF-1 + UNG2 – X-ray solution - HIV-1 
[[1x9v]] – Dimeric structure of the Vpr C-terminal domain - NMR 
[[1vpc]] - C-terminal domain of Vpr - NMR - HIV-1 
[[1fi0]] - Vpr residues 13-33 in micelles - NMR - HIV-1 
[[1bde]] - NMR solution of Vpr peptides connected to cell cycle arrest and nuclear provirus transfer 
[[5b56]] - Importin subunit alpha-1 + Vpr C-terminal domain - crystallographic analysis 
[[1kzs]], [[1kzt]], [[1kzv]] - Vpr residues 34-51 - NMR - HIV-1 
[[1dsj]] - Vpr residues 50-75 - NMR - HIV-1 
[[1ceu]] - Vpr N-terminal domain - NMR - HIV-1 
[[1dsk]] - Vpr residues 59-86 - NMR - HIV-1 

== References ==
<references/>
[[Category:Topic Page]]

Vpr protein

2018-04-09T12:54:22Z

Elia Shlush:

<StructureSection load='1m8l' size='300' side='right' caption='NMR structure of the HIV-1 Regulatory Protein Vpr' scene=''>

== Function ==
'''Vpr protein''' (Vpr) or '''viral protein R''' is a 96 amino acid protein which encoded by the human Immunodeﬁciency virus type 1 ([[HIV-1]]). HIV-1 genome includes nine genes, six of them are accessory proteins, including ''vpr''. Vpr has several roles in the progression of acquired immunodeficiency syndrome ([https://en.wikipedia.org/wiki/AIDS AIDS]) disease, including regulation the HIV-1 pre-integration complex ([https://en.wikipedia.org/wiki/Pre-integration_complex PIC]) nuclear import and virus replication in non-dividing macrophages<ref name='Morellet2003'>PMID:12614620</ref>. Moreover, Vpr prevents mitosis of dividing infect cells by blockade at G2 phase, when the viral promoter is more active, and induced apoptosis of these cells in G1 and M phase. Both the activities of cell cycle arrest and induce apoptosis has proven to be independence by mutations that can cause only one of these affects<ref name='Gonzalez2017'>PMID:28075409</ref>.

=== Vpr induce cell cycle arrest by recruits cellular targets for degradation<ref name='Wu2016'>PMID:27571178</ref> ===
One phenotype of Vpr expression is the induction of cell cycle arrest in G2 phase. This arrest executes by engaging of <scene name='75/750237/Ddb1/2'>DNA damage–binding protein 1 (DDB1)</scene> and CUL4A-associated factor 1 (DCAF1) to Vpr. DCAF1 is a substrate receptor of the Cullin4–RING E3 ubiquitin ligase (CRL4) of the host ubiquitin–proteasome-mediated protein degradation pathway. Mutations in Vpr that abolish its interaction with DCAF1, or silencing of DCAF1, eliminate cell-cycle arrest. The crystal structure of <scene name='75/750237/Vpr_ddb1_dcaf1_ung2/2'>DDB1–DCAF1–HIV-1–Vpr–uracil-DNA glycosylase (UNG2) complex</scene> elucidate the molecular mechanism in which Vpr inhibits UNG2 enzymatic activity and send it for degradation:
DCAF1 WD40 domain <scene name='75/750237/Dcaf1_vpr/1'>binds to Vpr</scene> by its N-terminus and α3 helix. In addition, DCAF1 is anchored into DDB1 by a helix-loop-helix motif. These motifs are commonly found in substrate receptor proteins that bind to DDB1. Finally, Vpr uses structural mimicry to DNA to <scene name='75/750237/Dcaf1_ung2/1'>engages UNG2</scene>. It interacts with UNG2 by residues in the hydrophobic cleft and an insert loop (residues 266–283), which mimics the phosphate backbone in the DNA. When interacts with DNA, UNG2 Leu272 residue uses to insert into the minor groove. The importance of Leu272 residue to UNG2-Vpr interaction was demonstrated by mutagenesis. Thus, Vpr recruite the CRL4–DCAF1 E3 ubiquitin ligase and targets cellular substrates for degradation. The reason for UNG2 degradation is not clear yet. However, their is a possibility that UNG2 exerts a negative effect on HIV-1 replication.

== Disease ==
HIV-1 retrovirus is the cause of AIDS disease. HIV-1 is a RNA virus which copy its genome to the host-cell genome in infect cells. HIV-1 infects activated CD4 immune cells and macrophages. When the disease is expressing in carriers, the progressive depletion of CD4 T cells causes immunodeficiency<ref name='Emerman1996'>PMID:8805364</ref>.
For more details about AIDS disease see {{Wikipedia|AIDS}}
For details about another HIV-1 components and its replication pathway see [[HIV and accessory proteins]].

== Relevance ==
According to 2017, the currently approved anti-HIV drugs target the Pol and Env encoded proteins. These drugs are effective in reducing viral replication. Thus, because of spontaneous mutations that occur during viral replication, drug resistance is evolve<ref>PMID:28681118</ref>. Understanding of Vpr structure and molecular mechanism may facilitate the design of HIV-1 antiviral therapy by its inhibition. Deletion of both ''vpr'' and ''vpx'' genes in SIV, which their protein products in SIV combine Vpr function in HIV-1, eliminate virus replication<ref name='Emerman1996'/>. The multiple significant functions that Vpr fills in HIV-1 replication makes it an attractive candidate for antiviral therapy<ref name='Gonzalez2017'/>.

== Conservation ==
Vpr is <scene name='75/750237/Conservation/3'>highly conserved</scene> in HIV and simian immunodeficiency virus (SIV), similar retrovirus which infects non-human primates<ref name='Morellet2003'/>. In addition, all primate lentiviruses has Vpr gene whose protein product has highly conserved motifs. HIV-2 and SIVsm lentiviruses have additionally gene - Vpx. In these lentiviruses, Vpr and Vpx executes together the roles which HIV-1 Vpr perform. Vpr and Vpx has low conservation between them<ref name='Emerman1996'/>. However, Vpr and Vpx families of proteins use related structural regions to bind and recruit cellular targets to the E3 ligase complex for degradation by the proteasome<ref name='Wu2016'/>. 
[[Image:Consurf_key_small.gif|200px|right]]

</StructureSection>

== 3D Structures of Vpr protein ==

Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}

[[1m8l]] – Vpr - NMR - HIV-1 
[[1esx]] - synthetic Vpr - NMR - HIV-1 
[[5jk7]] – Vpr + DDB1 + DCAF-1 + UNG2 – X-ray solution - HIV-1 
[[1x9v]] – Dimeric structure of the Vpr C-terminal domain - NMR 
[[1vpc]] - C-terminal domain of Vpr - NMR - HIV-1 
[[1fi0]] - Vpr residues 13-33 in micelles - NMR - HIV-1 
[[1bde]] - NMR solution of Vpr peptides connected to cell cycle arrest and nuclear provirus transfer 
[[5b56]] - Importin subunit alpha-1 + Vpr C-terminal domain - crystallographic analysis 
[[1kzs]], [[1kzt]], [[1kzv]] - Vpr residues 34-51 - NMR - HIV-1 
[[1dsj]] - Vpr residues 50-75 - NMR - HIV-1 
[[1ceu]] - Vpr N-terminal domain - NMR - HIV-1 
[[1dsk]] - Vpr residues 59-86 - NMR - HIV-1 

== References ==
<references/>
[[Category:Topic Page]]

Vpr protein

2018-04-09T11:42:20Z

Elia Shlush:

<StructureSection load='1m8l' size='300' side='right' caption='NMR structure of the HIV-1 Regulatory Protein Vpr' scene=''>

== Function ==
'''Vpr protein''' (Vpr) or '''viral protein R''' is a 96 amino acid protein which encoded by the human Immunodeﬁciency virus type 1 ([[HIV-1]]). HIV-1 genome includes nine genes, six of them are accessory proteins, including ''vpr''. Vpr has several roles in the progression of acquired immunodeficiency syndrome ([https://en.wikipedia.org/wiki/AIDS AIDS]) disease, including regulation the HIV-1 pre-integration complex ([https://en.wikipedia.org/wiki/Pre-integration_complex PIC]) nuclear import and virus replication in non-dividing macrophages<ref name='Morellet2003'>PMID:12614620</ref>. Moreover, Vpr prevents mitosis of dividing infect cells by blockade at G2 phase, when the viral promoter is more active, and induced apoptosis of these cells in G1 and M phase. Both the activities of cell cycle arrest and induce apoptosis has proven to be independence by mutations that can cause only one of these affects<ref name='Gonzalez2017'>PMID:28075409</ref>.

=== Vpr induce cell cycle arrest by recruits cellular targets for degradation<ref name='Wu2016'>PMID:27571178</ref> ===
One phenotype of Vpr expression is the induction of cell cycle arrest in G2 phase. This arrest executes by engaging of <scene name='75/750237/Ddb1/2'>DNA damage–binding protein 1 (DDB1)</scene> and CUL4A-associated factor 1 (DCAF1) to Vpr. DCAF1 is a substrate receptor of the Cullin4–RING E3 ubiquitin ligase (CRL4) of the host ubiquitin–proteasome-mediated protein degradation pathway. Mutations in Vpr that abolish its interaction with DCAF1, or silencing of DCAF1, eliminate cell-cycle arrest. The crystal structure of <scene name='75/750237/Vpr_ddb1_dcaf1_ung2/2'>DDB1–DCAF1–HIV-1–Vpr–uracil-DNA glycosylase (UNG2) complex</scene> elucidate the molecular mechanism in which Vpr inhibits UNG2 enzymatic activity and send it for degradation:
DCAF1 WD40 domain binds to Vpr by its N-terminus and α3 helix. In addition, DCAF1 is anchored into DDB1 by a helix-loop-helix motif. These motifs are commonly found in substrate receptor proteins that bind to DDB1. Finally, Vpr uses structural mimicry to DNA to engages UNG2. It interacts with UNG2 by residues in the hydrophobic cleft and an insert loop (residues 266–283), which mimics the phosphate backbone in the DNA. When interacts with DNA, UNG2 Leu272 residue uses to insert into the minor groove. The importance of Leu272 residue to UNG2-Vpr interaction was demonstrated by mutagenesis. Thus, Vpr recruite the CRL4–DCAF1 E3 ubiquitin ligase and targets cellular substrates for degradation. The reason for UNG2 degradation is not clear yet. However, their is a possibility that UNG2 exerts a negative effect on HIV-1 replication.

== Disease ==
HIV-1 retrovirus is the cause of AIDS disease. HIV-1 is a RNA virus which copy its genome to the host-cell genome in infect cells. HIV-1 infects activated CD4 immune cells and macrophages. When the disease is expressing in carriers, the progressive depletion of CD4 T cells causes immunodeficiency<ref name='Emerman1996'>PMID:8805364</ref>.
For more details about AIDS disease see {{Wikipedia|AIDS}}
For details about another HIV-1 components and its replication pathway see [[HIV and accessory proteins]].

== Relevance ==
According to 2017, the currently approved anti-HIV drugs target the Pol and Env encoded proteins. These drugs are effective in reducing viral replication. Thus, because of spontaneous mutations that occur during viral replication, drug resistance is evolve<ref>PMID:28681118</ref>. Understanding of Vpr structure and molecular mechanism may facilitate the design of HIV-1 antiviral therapy by its inhibition. Deletion of both ''vpr'' and ''vpx'' genes in SIV, which their protein products in SIV combine Vpr function in HIV-1, eliminate virus replication<ref name='Emerman1996'/>. The multiple significant functions that Vpr fills in HIV-1 replication makes it an attractive candidate for antiviral therapy<ref name='Gonzalez2017'/>.

== Conservation ==
Vpr is <scene name='75/750237/Conservation/3'>highly conserved</scene> in HIV and simian immunodeficiency virus (SIV), similar retrovirus which infects non-human primates<ref name='Morellet2003'/>. In addition, all primate lentiviruses has Vpr gene whose protein product has highly conserved motifs. HIV-2 and SIVsm lentiviruses have additionally gene - Vpx. In these lentiviruses, Vpr and Vpx executes together the roles which HIV-1 Vpr perform. Vpr and Vpx has low conservation between them<ref name='Emerman1996'/>. However, Vpr and Vpx families of proteins use related structural regions to bind and recruit cellular targets to the E3 ligase complex for degradation by the proteasome<ref name='Wu2016'/>. 
[[Image:Consurf_key_small.gif|200px|right]]

</StructureSection>

== 3D Structures of Vpr protein ==

Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}

[[1m8l]] – Vpr - NMR - HIV-1 
[[1esx]] - synthetic Vpr - NMR - HIV-1 
[[5jk7]] – Vpr + DDB1 + DCAF-1 + UNG2 – X-ray solution - HIV-1 
[[1x9v]] – Dimeric structure of the Vpr C-terminal domain - NMR 
[[1vpc]] - C-terminal domain of Vpr - NMR - HIV-1 
[[1fi0]] - Vpr residues 13-33 in micelles - NMR - HIV-1 
[[1bde]] - NMR solution of Vpr peptides connected to cell cycle arrest and nuclear provirus transfer 
[[5b56]] - Importin subunit alpha-1 + Vpr C-terminal domain - crystallographic analysis 
[[1kzs]], [[1kzt]], [[1kzv]] - Vpr residues 34-51 - NMR - HIV-1 
[[1dsj]] - Vpr residues 50-75 - NMR - HIV-1 
[[1ceu]] - Vpr N-terminal domain - NMR - HIV-1 
[[1dsk]] - Vpr residues 59-86 - NMR - HIV-1 

== References ==
<references/>
[[Category:Topic Page]]

Vpr protein

2018-04-09T11:33:53Z

Elia Shlush:

<StructureSection load='1m8l' size='300' side='right' caption='NMR structure of the HIV-1 Regulatory Protein Vpr' scene=''>

== Function ==
'''Vpr protein''' (Vpr) or '''viral protein R''' is a 96 amino acid protein which encoded by the human Immunodeﬁciency virus type 1 ([[HIV-1]]). HIV-1 genome includes nine genes, six of them are accessory proteins, including ''vpr''. Vpr has several roles in the progression of acquired immunodeficiency syndrome ([https://en.wikipedia.org/wiki/AIDS AIDS]) disease, including regulation the HIV-1 pre-integration complex ([https://en.wikipedia.org/wiki/Pre-integration_complex PIC]) nuclear import and virus replication in non-dividing macrophages<ref name='Morellet2003'>PMID:12614620</ref>. Moreover, Vpr prevents mitosis of dividing infect cells by blockade at G2 phase, when the viral promoter is more active, and induced apoptosis of these cells in G1 and M phase. Both the activities of cell cycle arrest and induce apoptosis has proven to be independence by mutations that can cause only one of these affects<ref name='Gonzalez2017'>PMID:28075409</ref>.

=== Vpr induce cell cycle arrest by recruits cellular targets for degradation<ref name='Wu2016'>PMID:27571178</ref> ===
One phenotype of Vpr expression is the induction of cell cycle arrest in G2 phase. This arrest executes by engaging of <scene name='75/750237/Ddb1/1'>DNA damage–binding protein 1 (DDB1)</scene> and CUL4A-associated factor 1 (DCAF1) to Vpr. DCAF1 is a substrate receptor of the Cullin4–RING E3 ubiquitin ligase (CRL4) of the host ubiquitin–proteasome-mediated protein degradation pathway. Mutations in Vpr that abolish its interaction with DCAF1, or silencing of DCAF1, eliminate cell-cycle arrest. The crystal structure of <scene name='75/750237/Vpr_ddb1_dcaf1_ung2/2'>DDB1–DCAF1–HIV-1–Vpr–uracil-DNA glycosylase (UNG2) complex</scene> elucidate the molecular mechanism in which Vpr inhibits UNG2 enzymatic activity and send it for degradation:
DCAF1 WD40 domain binds to Vpr by its N-terminus and α3 helix. In addition, DCAF1 is anchored into DDB1 by a helix-loop-helix motif. These motifs are commonly found in substrate receptor proteins that bind to DDB1. Finally, Vpr uses structural mimicry to DNA to engages UNG2. It interacts with UNG2 by residues in the hydrophobic cleft and an insert loop (residues 266–283), which mimics the phosphate backbone in the DNA. When interacts with DNA, UNG2 Leu272 residue uses to insert into the minor groove. The importance of Leu272 residue to UNG2-Vpr interaction was demonstrated by mutagenesis. Thus, Vpr recruite the CRL4–DCAF1 E3 ubiquitin ligase and targets cellular substrates for degradation. The reason for UNG2 degradation is not clear yet. However, their is a possibility that UNG2 exerts a negative effect on HIV-1 replication.

== Disease ==
HIV-1 retrovirus is the cause of AIDS disease. HIV-1 is a RNA virus which copy its genome to the host-cell genome in infect cells. HIV-1 infects activated CD4 immune cells and macrophages. When the disease is expressing in carriers, the progressive depletion of CD4 T cells causes immunodeficiency<ref name='Emerman1996'>PMID:8805364</ref>.
For more details about AIDS disease see {{Wikipedia|AIDS}}
For details about another HIV-1 components and its replication pathway see [[HIV and accessory proteins]].

== Relevance ==
According to 2017, the currently approved anti-HIV drugs target the Pol and Env encoded proteins. These drugs are effective in reducing viral replication. Thus, because of spontaneous mutations that occur during viral replication, drug resistance is evolve<ref>PMID:28681118</ref>. Understanding of Vpr structure and molecular mechanism may facilitate the design of HIV-1 antiviral therapy by its inhibition. Deletion of both ''vpr'' and ''vpx'' genes in SIV, which their protein products in SIV combine Vpr function in HIV-1, eliminate virus replication<ref name='Emerman1996'/>. The multiple significant functions that Vpr fills in HIV-1 replication makes it an attractive candidate for antiviral therapy<ref name='Gonzalez2017'/>.

== Conservation ==
Vpr is <scene name='75/750237/Conservation/3'>highly conserved</scene> in HIV and simian immunodeficiency virus (SIV), similar retrovirus which infects non-human primates<ref name='Morellet2003'/>. In addition, all primate lentiviruses has Vpr gene whose protein product has highly conserved motifs. HIV-2 and SIVsm lentiviruses have additionally gene - Vpx. In these lentiviruses, Vpr and Vpx executes together the roles which HIV-1 Vpr perform. Vpr and Vpx has low conservation between them<ref name='Emerman1996'/>. However, Vpr and Vpx families of proteins use related structural regions to bind and recruit cellular targets to the E3 ligase complex for degradation by the proteasome<ref name='Wu2016'/>. 
[[Image:Consurf_key_small.gif|200px|right]]

</StructureSection>

== 3D Structures of Vpr protein ==

Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}

[[1m8l]] – Vpr - NMR - HIV-1 
[[1esx]] - synthetic Vpr - NMR - HIV-1 
[[5jk7]] – Vpr + DDB1 + DCAF-1 + UNG2 – X-ray solution - HIV-1 
[[1x9v]] – Dimeric structure of the Vpr C-terminal domain - NMR 
[[1vpc]] - C-terminal domain of Vpr - NMR - HIV-1 
[[1fi0]] - Vpr residues 13-33 in micelles - NMR - HIV-1 
[[1bde]] - NMR solution of Vpr peptides connected to cell cycle arrest and nuclear provirus transfer 
[[5b56]] - Importin subunit alpha-1 + Vpr C-terminal domain - crystallographic analysis 
[[1kzs]], [[1kzt]], [[1kzv]] - Vpr residues 34-51 - NMR - HIV-1 
[[1dsj]] - Vpr residues 50-75 - NMR - HIV-1 
[[1ceu]] - Vpr N-terminal domain - NMR - HIV-1 
[[1dsk]] - Vpr residues 59-86 - NMR - HIV-1 

== References ==
<references/>
[[Category:Topic Page]]

Vpr protein

2018-04-09T11:30:00Z

Elia Shlush:

<StructureSection load='1m8l' size='300' side='right' caption='NMR structure of the HIV-1 Regulatory Protein Vpr' scene=''>

== Function ==
'''Vpr protein''' (Vpr) or '''viral protein R''' is a 96 amino acid protein which encoded by the human Immunodeﬁciency virus type 1 ([[HIV-1]]). HIV-1 genome includes nine genes, six of them are accessory proteins, including ''vpr''. Vpr has several roles in the progression of acquired immunodeficiency syndrome ([https://en.wikipedia.org/wiki/AIDS AIDS]) disease, including regulation the HIV-1 pre-integration complex ([https://en.wikipedia.org/wiki/Pre-integration_complex PIC]) nuclear import and virus replication in non-dividing macrophages<ref name='Morellet2003'>PMID:12614620</ref>. Moreover, Vpr prevents mitosis of dividing infect cells by blockade at G2 phase, when the viral promoter is more active, and induced apoptosis of these cells in G1 and M phase. Both the activities of cell cycle arrest and induce apoptosis has proven to be independence by mutations that can cause only one of these affects<ref name='Gonzalez2017'>PMID:28075409</ref>.

=== Vpr induce cell cycle arrest by recruits cellular targets for degradation<ref name='Wu2016'>PMID:27571178</ref> ===
One phenotype of Vpr expression is the induction of cell cycle arrest in G2 phase. This arrest executes by engaging of <scene name='75/750237/Ddb1/1'>DNA damage–binding protein 1 (DDB1)</scene> and CUL4A-associated factor 1 (DCAF1) to Vpr. DCAF1 is a substrate receptor of the Cullin4–RING E3 ubiquitin ligase (CRL4) of the host ubiquitin–proteasome-mediated protein degradation pathway. Mutations in Vpr that abolish its interaction with DCAF1, or silencing of DCAF1, eliminate cell-cycle arrest. The crystal structure of <scene name='75/750237/Vpr_ddb1_dcaf1_ung2/2'>DDB1–DCAF1–HIV-1–Vpr–uracil-DNA glycosylase (UNG2) complex</scene> elucidate the molecular mechanism in which Vpr inhibits UNG2 enzymatic activity and send it for degradation:
DCAF1 WD40 domain binds to Vpr by its N-terminus and α3 helix. In addition, DCAF1 is anchored into DDB1 by a helix-loop-helix motif. These motifs are commonly found in substrate receptor proteins that bind to DDB1. Finally, Vpr uses structural mimicry to DNA to engages UNG2. It interacts with UNG2 by residues in the hydrophobic cleft and an insert loop (residues 266–283), which mimics the phosphate backbone in the DNA. When interacts with DNA, UNG2 Leu272 residue uses to insert into the minor groove. The importance of Leu272 residue to UNG2-Vpr interaction was demonstrated by mutagenesis. Thus, Vpr recruite the CRL4–DCAF1 E3 ubiquitin ligase and targets cellular substrates for degradation. The reason for UNG2 degradation is not clear yet. However, their is a possibility that UNG2 exerts a negative effect on HIV-1 replication.

== Disease ==
HIV-1 retrovirus is the cause of AIDS disease. HIV-1 is a RNA virus which copy its genome to the host-cell genome in infect cells. HIV-1 infects activated CD4 immune cells and macrophages. When the disease is expressing in carriers, the progressive depletion of CD4 T cells causes immunodeficiency<ref name='Emerman1996'>PMID:8805364</ref>.
For more details about AIDS disease see {{Wikipedia|AIDS}}
For details about another HIV-1 components and its replication pathway see [[HIV and accessory proteins]].

== Relevance ==
According to 2017, the currently approved anti-HIV drugs target the Pol and Env encoded proteins. These drugs are effective in reducing viral replication. Thus, because of spontaneous mutations that occur during viral replication, drug resistance is evolve<ref>PMID:28681118</ref>. Understanding of Vpr structure and molecular mechanism may facilitate the design of HIV-1 antiviral therapy by its inhibition. Deletion of both ''vpr'' and ''vpx'' genes in SIV, which their protein products in SIV combine Vpr function in HIV-1, eliminate virus replication<ref name='Emerman1996'/>. The multiple significant functions that Vpr fills in HIV-1 replication makes it an attractive candidate for antiviral therapy<ref name='Gonzalez2017'/>.

== Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Vpr is <scene name='75/750237/Conservation/3'>highly conserved</scene> in HIV and simian immunodeficiency virus (SIV), similar retrovirus which infects non-human primates<ref name='Morellet2003'/>. In addition, all primate lentiviruses has Vpr gene whose protein product has highly conserved motifs. HIV-2 and SIVsm lentiviruses have additionally gene - Vpx. In these lentiviruses, Vpr and Vpx executes together the roles which HIV-1 Vpr perform. Vpr and Vpx has low conservation between them<ref name='Emerman1996'/>. However, Vpr and Vpx families of proteins use related structural regions to bind and recruit cellular targets to the E3 ligase complex for degradation by the proteasome<ref name='Wu2016'/>.

</StructureSection>

== 3D Structures of Vpr protein ==

Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}

[[1m8l]] – Vpr - NMR - HIV-1 
[[1esx]] - synthetic Vpr - NMR - HIV-1 
[[5jk7]] – Vpr + DDB1 + DCAF-1 + UNG2 – X-ray solution - HIV-1 
[[1x9v]] – Dimeric structure of the Vpr C-terminal domain - NMR 
[[1vpc]] - C-terminal domain of Vpr - NMR - HIV-1 
[[1fi0]] - Vpr residues 13-33 in micelles - NMR - HIV-1 
[[1bde]] - NMR solution of Vpr peptides connected to cell cycle arrest and nuclear provirus transfer 
[[5b56]] - Importin subunit alpha-1 + Vpr C-terminal domain - crystallographic analysis 
[[1kzs]], [[1kzt]], [[1kzv]] - Vpr residues 34-51 - NMR - HIV-1 
[[1dsj]] - Vpr residues 50-75 - NMR - HIV-1 
[[1ceu]] - Vpr N-terminal domain - NMR - HIV-1 
[[1dsk]] - Vpr residues 59-86 - NMR - HIV-1 

== References ==
<references/>
[[Category:Topic Page]]

Vpr protein

2018-04-09T10:58:00Z

Elia Shlush:

<StructureSection load='1m8l' size='300' side='right' caption='NMR structure of the HIV-1 Regulatory Protein Vpr' scene=''>

== Function ==
'''Vpr protein''' (Vpr) or '''viral protein R''' is a 96 amino acid protein which encoded by the human Immunodeﬁciency virus type 1 ([[HIV-1]]). HIV-1 genome includes nine genes, six of them are accessory proteins, including ''vpr''. Vpr has several roles in the progression of acquired immunodeficiency syndrome ([https://en.wikipedia.org/wiki/AIDS AIDS]) disease, including regulation the HIV-1 pre-integration complex ([https://en.wikipedia.org/wiki/Pre-integration_complex PIC]) nuclear import and virus replication in non-dividing macrophages<ref name='Morellet2003'>PMID:12614620</ref>. Moreover, Vpr prevents mitosis of dividing infect cells by blockade at G2 phase, when the viral promoter is more active, and induced apoptosis of these cells in G1 and M phase. Both the activities of cell cycle arrest and induce apoptosis has proven to be independence by mutations that can cause only one of these affects<ref name='Gonzalez2017'>PMID:28075409</ref>.

=== Vpr induce cell cycle arrest by recruits cellular targets for degradation<ref>PMID:27571178</ref> ===
One phenotype of Vpr expression is the induction of cell cycle arrest in G2 phase. This arrest executes by engaging of <scene name='75/750237/Ddb1/1'>DNA damage–binding protein 1 (DDB1)</scene> and CUL4A-associated factor 1 (DCAF1) to Vpr. DCAF1 is a substrate receptor of the Cullin4–RING E3 ubiquitin ligase (CRL4) of the host ubiquitin–proteasome-mediated protein degradation pathway. Mutations in Vpr that abolish its interaction with DCAF1, or silencing of DCAF1, eliminate cell-cycle arrest. The crystal structure of <scene name='75/750237/Vpr_ddb1_dcaf1_ung2/2'>DDB1–DCAF1–HIV-1–Vpr–uracil-DNA glycosylase (UNG2) complex</scene> elucidate the molecular mechanism in which Vpr inhibits UNG2 enzymatic activity and send it for degradation:
DCAF1 WD40 domain binds to Vpr by its N-terminus and α3 helix. In addition, DCAF1 is anchored into DDB1 by a helix-loop-helix motif. These motifs are commonly found in substrate receptor proteins that bind to DDB1. Finally, Vpr uses structural mimicry to DNA to engages UNG2. It interacts with UNG2 by residues in the hydrophobic cleft and an insert loop (residues 266–283), which mimics the phosphate backbone in the DNA. When interacts with DNA, UNG2 Leu272 residue uses to insert into the minor groove. The importance of Leu272 residue to UNG2-Vpr interaction was demonstrated by mutagenesis. Thus, Vpr recruite the CRL4–DCAF1 E3 ubiquitin ligase and targets cellular substrates for degradation. The reason for UNG2 degradation is not clear yet. However, their is a possibility that UNG2 exerts a negative effect on HIV-1 replication.

== Disease ==
HIV-1 retrovirus is the cause of AIDS disease. HIV-1 is a RNA virus which copy its genome to the host-cell genome in infect cells. HIV-1 infects activated CD4 immune cells and macrophages. When the disease is expressing in carriers, the progressive depletion of CD4 T cells causes immunodeficiency<ref name='Emerman1996'>PMID:8805364</ref>.
For more details about AIDS disease see {{Wikipedia|AIDS}}
For details about another HIV-1 components and its replication pathway see [[HIV and accessory proteins]].

== Relevance ==
Understanding of Vpr structure and molecular mechanism may facilitate the design of HIV-1 antiviral therapy by its inhibition. Deletion of both ''vpr'' and ''vpx'' genes in SIV, which their protein products in SIV combine Vpr function in HIV-1, eliminate virus replication<ref name='Emerman1996'/>. The multiple significant functions that Vpr fills in HIV-1 replication makes it an attractive candidate for antiviral therapy <ref name='Gonzalez2017'/>

== Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Vpr is <scene name='75/750237/Conservation/3'>highly conserved</scene> in HIV and simian immunodeficiency virus (SIV), similar retrovirus which infects non-human primates<ref name='Morellet2003'/>. In addition, all primate lentiviruses has vpr gene whose protein product has highly conserved motifs. HIV-2 and SIVsm lentiviruses have additionally gene - vpx. In these lentiviruses, vpr and vpx executes together the roles which HIV-1 vpr perform. Vpr and Vpx has low conservation between them.

</StructureSection>

== 3D Structures of Vpr protein ==

Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}

[[1m8l]] – Vpr - NMR - HIV-1 
[[1esx]] - synthetic Vpr - NMR - HIV-1 
[[5jk7]] – Vpr + DDB1 + DCAF-1 + UNG2 – X-ray solution - HIV-1 
[[1x9v]] – Dimeric structure of the Vpr C-terminal domain - NMR 
[[1vpc]] - C-terminal domain of Vpr - NMR - HIV-1 
[[1fi0]] - Vpr residues 13-33 in micelles - NMR - HIV-1 
[[1bde]] - NMR solution of Vpr peptides connected to cell cycle arrest and nuclear provirus transfer 
[[5b56]] - Importin subunit alpha-1 + Vpr C-terminal domain - crystallographic analysis 
[[1kzs]], [[1kzt]], [[1kzv]] - Vpr residues 34-51 - NMR - HIV-1 
[[1dsj]] - Vpr residues 50-75 - NMR - HIV-1 
[[1ceu]] - Vpr N-terminal domain - NMR - HIV-1 
[[1dsk]] - Vpr residues 59-86 - NMR - HIV-1 

== References ==
<references/>
[[Category:Topic Page]]

Vpr protein

2018-04-08T07:41:42Z

Elia Shlush:

Vpr protein

2018-04-08T07:35:18Z

Elia Shlush:

Vpr protein

2018-04-08T07:15:49Z

Elia Shlush:

Vpr protein

2018-04-08T00:49:13Z

Elia Shlush:

Vpr protein

2018-04-08T00:32:04Z

Elia Shlush:

<StructureSection load='5jk7' size='340' side='right' caption='HIV-1 Vpr protein (cyan) complex with Human DNA damage-binding protein (grey), VPRBP (pink) and Uracyl-DNA glycosylase (yellow) (PDB code [[5jk7]])' scene=''>

== Function ==
'''Vpr protein''' (Vpr) or '''viral protein R''' is a 96 amino acid protein which encoded by the human Immunodeﬁciency virus type 1 ([[HIV-1]]). HIV-1 genome includes nine genes, six of them are accessory proteins, including ''vpr''. Vpr has several roles in the progression of acquired immunodeficiency syndrome ([https://en.wikipedia.org/wiki/AIDS AIDS]) disease, including regulation the HIV-1 pre-integration complex ([https://en.wikipedia.org/wiki/Pre-integration_complex PIC]) nuclear import and virus replication in non-dividing macrophages<ref name='Morellet2003'>PMID:12614620</ref>. Moreover, Vpr prevents mitosis of dividing infect cells by blockade at G2 phase, when the viral promoter is more active, and induced apoptosis of these cells in G1 and M phase. Both the activities of cell cycle arrest and induce apoptosis has proven to be independence by mutations that can cause only one of these affects<ref name='Gonzalez2017'>PMID:28075409</ref>.

=== Vpr induce cell cycle arrest by recruits cellular targets for degradation<ref>PMID:27571178</ref> ===
One phenotype of Vpr expression is the induction of cell cycle arrest in G2 phase. This arrest executes by engaging of DNA damage–binding protein 1 (DDB1) and CUL4A-associated factor 1 (DCAF1) to Vpr. DCAF1 is a substrate receptor of the Cullin4–RING E3 ubiquitin ligase (CRL4) of the host ubiquitin–proteasome-mediated protein degradation pathway. Mutations in Vpr that abolish its interaction with DCAF1, or silencing of DCAF1, eliminate cell-cycle arrest. The crystal structure of DDB1–DCAF1–HIV-1–Vpr–uracil-DNA glycosylase (UNG2) complex elucidate the molecular mechanism in which Vpr inhibits DDB1 enzymatic activity and send it for degradation.
* Vpr binding to the DCAF1 WD40 by its N-terminus and α3 helix. 
* Vpr uses structural mimicry to DNA to engages UNG2. 
* DCAF1 is anchored into DDB1 by a helix-loop-helix motif 

== Disease ==
HIV-1 retrovirus is the cause of AIDS disease. HIV-1 is a RNA virus which copy its genome to the host-cell genome in infect cells. HIV-1 infects activated CD4 immune cells and macrophages. When the disease is expressing in carriers, the progressive depletion of CD4 T cells causes immunodeficiency<ref name='Emerman1996'>PMID:8805364</ref>.
For more details about AIDS disease see {{Wikipedia|AIDS}}
For details about another HIV-1 components and its replication pathway see [[HIV and accessory proteins]].

== Relevance ==
Understanding of Vpr structure and molecular mechanism may facilitate the design of HIV-1 antiviral therapy by its inhibition. Deletion of both ''vpr'' and ''vpx'' genes in SIV, which their protein products in SIV combine Vpr function in HIV-1, eliminate virus replication<ref name='Emerman1996'/>. The multiple significant functions that Vpr fills in HIV-1 replication makes it an attractive candidate for antiviral therapy <ref name='Gonzalez2017'/>

== Conservation ==
Vpr is highly conserved in HIV and simian immunodeficiency virus (SIV), similar retrovirus which infects non-human primates<ref name='Morellet2003'/>. In addition, all primate lentiviruses has vpr gene whose protein product has highly conserved motifs. HIV-2 and SIVsm lentiviruses have additionally gene - vpx. In these lentiviruses, vpr and vpx executes together the roles which HIV-1 vpr perform. Vpr and Vpx has low conservation between them.

</StructureSection>

== 3D Structures of Vpr protein ==

Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}

[[1m8l]] – Vpr - NMR - HIV-1 
[[1esx]] - synthetic Vpr - NMR - HIV-1 
[[5jk7]] – Vpr + DDB1 + DCAF-1 + UNG2 – X-ray solution - HIV-1 
[[1x9v]] – Dimeric structure of the Vpr C-terminal domain - NMR 
[[1vpc]] - C-terminal domain of Vpr - NMR - HIV-1 
[[1fi0]] - Vpr residues 13-33 in micelles - NMR - HIV-1 
[[1bde]] - NMR solution of Vpr peptides connected to cell cycle arrest and nuclear provirus transfer 
[[5b56]] - Importin subunit alpha-1 + Vpr C-terminal domain - crystallographic analysis 
[[1kzs]], [[1kzt]], [[1kzv]] - Vpr residues 34-51 - NMR - HIV-1 
[[1dsj]] - Vpr residues 50-75 - NMR - HIV-1 
[[1ceu]] - Vpr N-terminal domain - NMR - HIV-1 
[[1dsk]] - Vpr residues 59-86 - NMR - HIV-1 

== References ==
<references/>
[[Category:Topic Page]]

Vpr protein

2018-04-08T00:11:55Z

Elia Shlush:

<StructureSection load='5jk7' size='340' side='right' caption='HIV-1 Vpr protein (cyan) complex with Human DNA damage-binding protein (grey), VPRBP (pink) and Uracyl-DNA glycosylase (yellow) (PDB code [[5jk7]])' scene=''>

== Function ==
'''Vpr protein''' (Vpr) or '''viral protein R''' is a 96 amino acid protein which encoded by the human Immunodeﬁciency virus type 1 ([[HIV-1]]). HIV-1 genome includes nine genes, six of them are accessory proteins, including ''vpr''. Vpr has several roles in the progression of acquired immunodeficiency syndrome ([https://en.wikipedia.org/wiki/AIDS AIDS]) disease, including regulation the HIV-1 pre-integration complex ([https://en.wikipedia.org/wiki/Pre-integration_complex PIC]) nuclear import and virus replication in non-dividing macrophages<ref name='Morellet2003'>PMID:12614620</ref>. Moreover, Vpr prevents mitosis of dividing infect cells by blockade at G2 phase, when the viral promoter is more active, and induced apoptosis of these cells in G1 and M phase. Both the activities of cell cycle arrest and induce apoptosis has proven to be independence by mutations that can cause only one of these affects<ref name='Gonzalez2017'>PMID:28075409</ref>.

=== Vpr induce cell cycle arrest by recruits cellular targets for degradation<ref>PMID:27571178</ref> ===
One phenotype of Vpr expression is the induction of cell cycle arrest in G2 phase. This arrest executes by engaging of DNA damage–binding protein 1 (DDB1) and CUL4A-associated factor 1 (DCAF1) to Vpr. DCAF1 is a substrate receptor of the Cullin4–RING E3 ubiquitin ligase (CRL4) of the host ubiquitin–proteasome-mediated protein degradation pathway. Mutations in Vpr that abolish its interaction with DCAF1, or silencing of DCAF1, eliminate cell-cycle arrest.

== Disease ==
HIV-1 retrovirus is the cause of AIDS disease. HIV-1 is a RNA virus which copy its genome to the host-cell genome in infect cells. HIV-1 infects activated CD4 immune cells and macrophages. When the disease is expressing in carriers, the progressive depletion of CD4 T cells causes immunodeficiency<ref name='Emerman1996'>PMID:8805364</ref>.
For more details about AIDS disease see {{Wikipedia|AIDS}}
For details about another HIV-1 components and its replication pathway see [[HIV and accessory proteins]].

== Relevance ==
Understanding of Vpr structure and molecular mechanism may facilitate the design of HIV-1 antiviral therapy by its inhibition. Deletion of both ''vpr'' and ''vpx'' genes in SIV, which their protein products in SIV combine Vpr function in HIV-1, eliminate virus replication<ref name='Emerman1996'/>. The multiple significant functions that Vpr fills in HIV-1 replication makes it an attractive candidate for antiviral therapy <ref name='Gonzalez2017'/>

== Conservation ==
Vpr is highly conserved in HIV and simian immunodeficiency virus (SIV), similar retrovirus which infects non-human primates<ref name='Morellet2003'/>. In addition, all primate lentiviruses has vpr gene whose protein product has highly conserved motifs. HIV-2 and SIVsm lentiviruses have additionally gene - vpx. In these lentiviruses, vpr and vpx executes together the roles which HIV-1 vpr perform. Vpr and Vpx has low conservation between them.

</StructureSection>

== 3D Structures of Vpr protein ==

Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}

[[1m8l]] – Vpr - NMR - HIV-1 
[[1esx]] - synthetic Vpr - NMR - HIV-1 
[[5jk7]] – Vpr + DDB1 + DCAF-1 + UNG2 – X-ray solution - HIV-1 
[[1x9v]] – Dimeric structure of the Vpr C-terminal domain - NMR 
[[1vpc]] - C-terminal domain of Vpr - NMR - HIV-1 
[[1fi0]] - Vpr residues 13-33 in micelles - NMR - HIV-1 
[[1bde]] - NMR solution of Vpr peptides connected to cell cycle arrest and nuclear provirus transfer 
[[5b56]] - Importin subunit alpha-1 + Vpr C-terminal domain - crystallographic analysis 
[[1kzs]], [[1kzt]], [[1kzv]] - Vpr residues 34-51 - NMR - HIV-1 
[[1dsj]] - Vpr residues 50-75 - NMR - HIV-1 
[[1ceu]] - Vpr N-terminal domain - NMR - HIV-1 
[[1dsk]] - Vpr residues 59-86 - NMR - HIV-1 

== References ==
<references/>
[[Category:Topic Page]]

Vpr protein

2018-04-07T23:44:07Z

Elia Shlush:

<StructureSection load='5jk7' size='340' side='right' caption='HIV-1 Vpr protein (cyan) complex with Human DNA damage-binding protein (grey), VPRBP (pink) and Uracyl-DNA glycosylase (yellow) (PDB code [[5jk7]])' scene=''>

== Function ==
'''Vpr protein''' (Vpr) or '''viral protein R''' is a 96 amino acid protein which encoded by the human Immunodeﬁciency virus type 1 ([[HIV-1]]). HIV-1 genome includes nine genes, six of them are accessory proteins, including ''vpr''. Vpr has several roles in the progression of acquired immunodeficiency syndrome ([https://en.wikipedia.org/wiki/AIDS AIDS]) disease, including regulation the HIV-1 pre-integration complex ([https://en.wikipedia.org/wiki/Pre-integration_complex PIC]) nuclear import and virus replication in non-dividing macrophages<ref name='Morellet2003'>PMID:12614620</ref>. Moreover, Vpr prevents mitosis of dividing infect cells by blockade at G2 phase, when the viral promoter is more active, and induced apoptosis of these cells in G1 and M phase. Both the activities of cell cycle arrest and induce apoptosis has proven to be independence by mutations that can cause only one of these affects<ref name='Gonzalez2017'>PMID:28075409</ref>.

== Disease ==
HIV-1 retrovirus is the cause of AIDS disease. HIV-1 is a RNA virus which copy its genome to the host-cell genome in infect cells. HIV-1 infects activated CD4 immune cells and macrophages. When the disease is expressing in carriers, the progressive depletion of CD4 T cells causes immunodeficiency<ref name='Emerman1996'>PMID:8805364</ref>.
For more details about AIDS disease see {{Wikipedia|AIDS}}
For details about another HIV-1 components and its replication pathway see [[HIV and accessory proteins]].

== Relevance ==
Understanding of Vpr structure and molecular mechanism may facilitate the design of HIV-1 antiviral therapy by its inhibition. Deletion of both ''vpr'' and ''vpx'' genes in SIV, which their protein products in SIV combine Vpr function in HIV-1, eliminate virus replication<ref name='Emerman1996'/>. The multiple significant functions that Vpr fills in HIV-1 replication makes it an attractive candidate for antiviral therapy <ref name='Gonzalez2017'/>

== Conservation ==
Vpr is highly conserved in HIV and simian immunodeficiency virus (SIV), similar retrovirus which infects non-human primates<ref name='Morellet2003'/>. In addition, all primate lentiviruses has vpr gene whose protein product has highly conserved motifs. HIV-2 and SIVsm lentiviruses have additionally gene - vpx. In these lentiviruses, vpr and vpx executes together the roles which HIV-1 vpr perform. Vpr and Vpx has low conservation between them.

</StructureSection>

== 3D Structures of Vpr protein ==

Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}

[[1m8l]] – Vpr - NMR - HIV-1 
[[1esx]] - synthetic Vpr - NMR - HIV-1 
[[5jk7]] – Vpr + DDB1 + DCAF-1 + UNG2 – X-ray solution - HIV-1 
[[1x9v]] – Dimeric structure of the Vpr C-terminal domain - NMR 
[[1vpc]] - C-terminal domain of Vpr - NMR - HIV-1 
[[1fi0]] - Vpr residues 13-33 in micelles - NMR - HIV-1 
[[1bde]] - NMR solution of Vpr peptides connected to cell cycle arrest and nuclear provirus transfer 
[[5b56]] - Importin subunit alpha-1 + Vpr C-terminal domain - crystallographic analysis 
[[1kzs]], [[1kzt]], [[1kzv]] - Vpr residues 34-51 - NMR - HIV-1 
[[1dsj]] - Vpr residues 50-75 - NMR - HIV-1 
[[1ceu]] - Vpr N-terminal domain - NMR - HIV-1 
[[1dsk]] - Vpr residues 59-86 - NMR - HIV-1 

== References ==
<references/>
[[Category:Topic Page]]

Vpr protein

2018-04-07T23:43:05Z

Elia Shlush:

<StructureSection load='5jk7' size='340' side='right' caption='HIV-1 Vpr protein (cyan) complex with Human DNA damage-binding protein (grey), VPRBP (pink) and Uracyl-DNA glycosylase (yellow) (PDB code [[5jk7]])' scene=''>

== Function ==
'''Vpr protein''' (Vpr) or '''viral protein R''' is a 96 amino acid protein which encoded by the human Immunodeﬁciency virus type 1 ([[HIV-1]]). HIV-1 genome includes nine genes, six of them are accessory proteins, including ''vpr''. Vpr has several roles in the progression of acquired immunodeficiency syndrome ([https://en.wikipedia.org/wiki/AIDS AIDS]) disease, including regulation the HIV-1 pre-integration complex ([https://en.wikipedia.org/wiki/Pre-integration_complex PIC]) nuclear import and virus replication in non-dividing macrophages<ref name='Morellet2003'>PMID:12614620</ref>. Moreover, Vpr prevents mitosis of dividing infect cells by blockade at G2 phase, when the viral promoter is more active, and induced apoptosis of these cells in G1 and M phase. Both the activities of cell cycle arrest and induce apoptosis has proven to be independence by mutations that can cause only one of these affects<ref name='Gonzalez2017'>PMID:28075409</ref>.

== Disease ==
HIV-1 retrovirus is the cause of AIDS disease. HIV-1 is a RNA virus which copy its genome to the host-cell genome in infect cells. HIV-1 infects activated CD4 immune cells and macrophages. When the disease is expressing in carriers, the progressive depletion of CD4 T cells causes immunodeficiency<ref name='Emerman1996'>PMID:8805364</ref>.
For more details about AIDS disease see {{Wikipedia|AIDS}}
For details about another HIV-1 components and its replication pathway see [[HIV and accessory proteins]].

== Relevance ==
Understanding of Vpr structure and molecular mechanism may facilitate the design of HIV-1 antiviral therapy by its inhibition. Deletion of both ''vpr'' and ''vpx'' genes in SIV, which their protein products in SIV combine Vpr function in HIV-1, eliminate virus replication<ref name='Emerman1996'/>. The multiple significant functions that Vpr fills in HIV-1 replication makes it an attractive candidate for antiviral therapy <ref name='Gonzalez2017'/>

== Conservation ==
Vpr is highly conserved in HIV and simian immunodeficiency virus (SIV), similar retrovirus which infects non-human primates<ref name='Morellet2003'/>. In addition, all primate lentiviruses has vpr gene whose protein product has highly conserved motifs. HIV-2 and SIVsm lentiviruses have additionally gene - vpx. In these lentiviruses, vpr and vpx executes together the roles which HIV-1 vpr perform. Vpr and Vpx has low conservation between them.

</StructureSection>

== 3D Structures of Vpr protein ==

Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}

[[1m8l]] – Vpr - NMR - HIV-1 
[[1esx]] - synthetic Vpr - NMR - HIV-1 
[[5jk7]] – Vpr + DDB1 + DCAF-1 + UNG2 – X-ray solution - HIV-1 
[[1x9v]] – Dimeric structure of the Vpr C-terminal domain - NMR 
[[1vpc]] - C-terminal domain of Vpr - NMR - HIV-1 
[[1fi0]] - Vpr residues 13-33 in micelles - NMR - HIV-1 
[[1bde]] - NMR solution of Vpr peptides connected to cell cycle arrest and nuclear provirus transfer 
[[5b56]] - Importin subunit alpha-1 + Vpr C-terminal domain - crystallographic analysis 
[[1kzs]], [[1kzt]], [[1kzv]] - Vpr residues 34-51 - NMR - HIV-1 
[[1dsj]] - Vpr residues 50-75 - NMR - HIV-1 
[[1ceu]] - Vpr N-terminal domain - NMR - HIV-1 
[[1dsk]] - Vpr residues 59-86 - NMR - HIV-1 

== References ==
<references/>
[[Category:Topic Page]]

Vpr protein

2018-04-07T21:41:14Z

Elia Shlush:

Vpr protein

2018-04-07T20:33:04Z

Elia Shlush:

Vpr protein

2018-04-07T19:04:44Z

Elia Shlush:

Vpr protein

2018-04-07T19:04:11Z

Elia Shlush:

Vpr protein

2018-04-03T19:38:10Z

Elia Shlush:

Vpr protein

2018-04-03T19:35:55Z

Elia Shlush:

Vpr protein

2018-04-03T19:13:30Z

Elia Shlush:

Vpr protein

2018-04-03T13:42:20Z

Elia Shlush:

Vpr protein

2018-04-03T13:14:31Z

Elia Shlush:

Vpr protein

2018-04-03T13:04:51Z

Elia Shlush:

Vpr protein

2018-04-03T12:21:42Z

Elia Shlush:

Vpr protein

2018-04-03T09:38:30Z

Elia Shlush:

Vpr protein

2018-04-02T19:02:52Z

Elia Shlush:

Vpr protein

2018-04-02T16:02:37Z

Elia Shlush:

Vpr protein

2018-04-02T15:34:38Z

Elia Shlush:

Vpr protein

2018-04-02T15:32:39Z

Elia Shlush:

Vpr protein

2018-04-02T10:12:17Z

Elia Shlush:

Vpr protein

2018-04-02T08:16:34Z

Elia Shlush: