4e91 - Revision history

OCA at 11:02, 1 March 2024

2024-03-01T11:02:36Z

← Older revision		Revision as of 11:02, 1 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4e91]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E91 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4E91 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4e91]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E91 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4E91 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0OE:4-{2-[5-(3-CHLOROPHENYL)-1H-PYRAZOL-4-YL]-1-[3-(1H-IMIDAZOL-1-YL)PROPYL]-1H-BENZIMIDAZOL-5-YL}BENZOIC+ACID'>0OE</scene>, <scene name='pdbligand=0OF:(3S)-1-ETHYL-3-[3-HYDROXY-5-(PYRIDIN-3-YL)PHENYL]-5-PHENYL-7-(TRIFLUOROMETHYL)-1H-1,5-BENZODIAZEPINE-2,4(3H,5H)-DIONE'>0OF</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>		</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.7Å</td></tr>
			<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0OE:4-{2-[5-(3-CHLOROPHENYL)-1H-PYRAZOL-4-YL]-1-[3-(1H-IMIDAZOL-1-YL)PROPYL]-1H-BENZIMIDAZOL-5-YL}BENZOIC+ACID'>0OE</scene>, <scene name='pdbligand=0OF:(3S)-1-ETHYL-3-[3-HYDROXY-5-(PYRIDIN-3-YL)PHENYL]-5-PHENYL-7-(TRIFLUOROMETHYL)-1H-1,5-BENZODIAZEPINE-2,4(3H,5H)-DIONE'>0OF</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4e91 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e91 OCA], [https://pdbe.org/4e91 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4e91 RCSB], [https://www.ebi.ac.uk/pdbsum/4e91 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4e91 ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4e91 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e91 OCA], [https://pdbe.org/4e91 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4e91 RCSB], [https://www.ebi.ac.uk/pdbsum/4e91 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4e91 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[[https://www.uniprot.org/uniprot/POL_HV1N5 POL_HV1N5]] Gag-Pol polyprotein and Gag polyprotein may regulate their own translation, by the binding genomic RNA in the 5'-UTR. At low concentration, Gag-Pol and Gag would promote translation, whereas at high concentration, the polyproteins encapsidate genomic RNA and then shutt off translation (By similarity). Matrix protein p17 has two main functions: in infected cell, it targets Gag and Gag-pol polyproteins to the plasma membrane via a multipartite membrane-binding signal, that includes its myristoylated N-terminus. The second function is to play a role in nuclear localization of the viral genome at the very start of cell infection. Matrix protein is the part of the pre-integration complex. It binds in the cytoplasm the human BAF protein which prevent autointegration of the viral genome, and might be included in virions at the ration of zero to 3 BAF dimer per virion. The myristoylation signal and the NLS thus exert conflicting influences its subcellular localization. The key regulation of these motifs might be phosphorylation of a portion of MA molecules on the C-terminal tyrosine at the time of virus maturation, by virion-associated cellular tyrosine kinase. Implicated in the release from host cell mediated by Vpu (By similarity). Capsid protein p24 forms the conical core that encapsulates the genomic RNA-nucleocapsid complex in the virion. Most core are conical, with only 7% tubular. The core is constituted by capsid protein hexamer subunits. The core is disassembled soon after virion entry. Interaction with human PPIA/CYPA protects the virus from restriction by human TRIM5-alpha and from an unknown antiviral activity in human cells. This capsid restriction by TRIM5 is one of the factors which restricts HIV-1 to the human species (By similarity). Nucleocapsid protein p7 encapsulates and protects viral dimeric unspliced (genomic) RNA. Binds these RNAs through its zinc fingers. Facilitates rearangement of nucleic acid secondary structure during retrotranscription of genomic RNA. This capability is referred to as nucleic acid chaperone activity (By similarity). The aspartyl protease mediates proteolytic cleavages of Gag and Gag-Pol polyproteins during or shortly after the release of the virion from the plasma membrane. Cleavages take place as an ordered, step-wise cascade to yield mature proteins. This process is called maturation. Displays maximal activity during the budding process just prior to particle release from the cell. Also cleaves Nef and Vif, probably concomitantly with viral structural proteins on maturation of virus particles (By similarity). Reverse transcriptase/ribonuclease H (RT) is a multifunctional enzyme that converts the viral RNA genome into dsDNA in the cytoplasm, shortly after virus entry into the cell. This enzyme displays a DNA polymerase activity that can copy either DNA or RNA templates, and a ribonuclease H (RNase H) activity that cleaves the RNA strand of RNA-DNA heteroduplexes in a partially processive 3' to 5' endonucleasic mode. Conversion of viral genomic RNA into dsDNA requires many steps. A tRNA(3)-Lys binds to the primer-binding site (PBS) situated at the 5'-end of the viral RNA. RT uses the 3' end of the tRNA primer to perform a short round of RNA-dependent minus-strand DNA synthesis. The reading proceeds through the U5 region and ends after the repeated (R) region which is present at both ends of viral RNA. The portion of the RNA-DNA heteroduplex is digested by the RNase H, resulting in a ssDNA product attached to the tRNA primer. This ssDNA/tRNA hybridizes with the identical R region situated at the 3' end of viral RNA. This template exchange, known as minus-strand DNA strong stop transfer, can be either intra- or intermolecular. RT uses the 3' end of this newly synthesized short ssDNA to perform the RNA-dependent minus-strand DNA synthesis of the whole template. RNase H digests the RNA template except for two polypurine tracts (PPTs) situated at the 5'-end and near the center of the genome. It is not clear if both polymerase and RNase H activities are simultaneous. RNase H probably can proceed both in a polymerase-dependent (RNA cut into small fragments by the same RT performing DNA synthesis) and a polymerase-independent mode (cleavage of remaining RNA fragments by free RTs). Secondly, RT performs DNA-directed plus-strand DNA synthesis using the PPTs that have not been removed by RNase H as primers. PPTs and tRNA primers are then removed by RNase H. The 3' and 5' ssDNA PBS regions hybridize to form a circular dsDNA intermediate. Strand displacement synthesis by RT to the PBS and PPT ends produces a blunt ended, linear dsDNA copy of the viral genome that includes long terminal repeats (LTRs) at both ends (By similarity). Integrase catalyzes viral DNA integration into the host chromosome, by performing a series of DNA cutting and joining reactions. This enzyme activity takes place after virion entry into a cell and reverse transcription of the RNA genome in dsDNA. The first step in the integration process is 3' processing. This step requires a complex comprising the viral genome, matrix protein, Vpr and integrase. This complex is called the pre-integration complex (PIC). The integrase protein removes 2 nucleotides from each 3' end of the viral DNA, leaving recessed CA OH's at the 3' ends. In the second step, the PIC enters cell nucleus. This process is mediated through integrase and Vpr proteins, and allows the virus to infect a non dividing cell. This ability to enter the nucleus is specific of lentiviruses, other retroviruses cannot and rely on cell division to access cell chromosomes. In the third step, termed strand transfer, the integrase protein joins the previously processed 3' ends to the 5' ends of strands of target cellular DNA at the site of integration. The 5'-ends are produced by integrase-catalyzed staggered cuts, 5 bp apart. A Y-shaped, gapped, recombination intermediate results, with the 5'-ends of the viral DNA strands and the 3' ends of target DNA strands remaining unjoined, flanking a gap of 5 bp. The last step is viral DNA integration into host chromosome. This involves host DNA repair synthesis in which the 5 bp gaps between the unjoined strands are filled in and then ligated. Since this process occurs at both cuts flanking the HIV genome, a 5 bp duplication of host DNA is produced at the ends of HIV-1 integration. Alternatively, Integrase may catalyze the excision of viral DNA just after strand transfer, this is termed disintegration (By similarity).		[https://www.uniprot.org/uniprot/POL_HV1N5 POL_HV1N5] Gag-Pol polyprotein and Gag polyprotein may regulate their own translation, by the binding genomic RNA in the 5'-UTR. At low concentration, Gag-Pol and Gag would promote translation, whereas at high concentration, the polyproteins encapsidate genomic RNA and then shutt off translation (By similarity). Matrix protein p17 has two main functions: in infected cell, it targets Gag and Gag-pol polyproteins to the plasma membrane via a multipartite membrane-binding signal, that includes its myristoylated N-terminus. The second function is to play a role in nuclear localization of the viral genome at the very start of cell infection. Matrix protein is the part of the pre-integration complex. It binds in the cytoplasm the human BAF protein which prevent autointegration of the viral genome, and might be included in virions at the ration of zero to 3 BAF dimer per virion. The myristoylation signal and the NLS thus exert conflicting influences its subcellular localization. The key regulation of these motifs might be phosphorylation of a portion of MA molecules on the C-terminal tyrosine at the time of virus maturation, by virion-associated cellular tyrosine kinase. Implicated in the release from host cell mediated by Vpu (By similarity). Capsid protein p24 forms the conical core that encapsulates the genomic RNA-nucleocapsid complex in the virion. Most core are conical, with only 7% tubular. The core is constituted by capsid protein hexamer subunits. The core is disassembled soon after virion entry. Interaction with human PPIA/CYPA protects the virus from restriction by human TRIM5-alpha and from an unknown antiviral activity in human cells. This capsid restriction by TRIM5 is one of the factors which restricts HIV-1 to the human species (By similarity). Nucleocapsid protein p7 encapsulates and protects viral dimeric unspliced (genomic) RNA. Binds these RNAs through its zinc fingers. Facilitates rearangement of nucleic acid secondary structure during retrotranscription of genomic RNA. This capability is referred to as nucleic acid chaperone activity (By similarity). The aspartyl protease mediates proteolytic cleavages of Gag and Gag-Pol polyproteins during or shortly after the release of the virion from the plasma membrane. Cleavages take place as an ordered, step-wise cascade to yield mature proteins. This process is called maturation. Displays maximal activity during the budding process just prior to particle release from the cell. Also cleaves Nef and Vif, probably concomitantly with viral structural proteins on maturation of virus particles (By similarity). Reverse transcriptase/ribonuclease H (RT) is a multifunctional enzyme that converts the viral RNA genome into dsDNA in the cytoplasm, shortly after virus entry into the cell. This enzyme displays a DNA polymerase activity that can copy either DNA or RNA templates, and a ribonuclease H (RNase H) activity that cleaves the RNA strand of RNA-DNA heteroduplexes in a partially processive 3' to 5' endonucleasic mode. Conversion of viral genomic RNA into dsDNA requires many steps. A tRNA(3)-Lys binds to the primer-binding site (PBS) situated at the 5'-end of the viral RNA. RT uses the 3' end of the tRNA primer to perform a short round of RNA-dependent minus-strand DNA synthesis. The reading proceeds through the U5 region and ends after the repeated (R) region which is present at both ends of viral RNA. The portion of the RNA-DNA heteroduplex is digested by the RNase H, resulting in a ssDNA product attached to the tRNA primer. This ssDNA/tRNA hybridizes with the identical R region situated at the 3' end of viral RNA. This template exchange, known as minus-strand DNA strong stop transfer, can be either intra- or intermolecular. RT uses the 3' end of this newly synthesized short ssDNA to perform the RNA-dependent minus-strand DNA synthesis of the whole template. RNase H digests the RNA template except for two polypurine tracts (PPTs) situated at the 5'-end and near the center of the genome. It is not clear if both polymerase and RNase H activities are simultaneous. RNase H probably can proceed both in a polymerase-dependent (RNA cut into small fragments by the same RT performing DNA synthesis) and a polymerase-independent mode (cleavage of remaining RNA fragments by free RTs). Secondly, RT performs DNA-directed plus-strand DNA synthesis using the PPTs that have not been removed by RNase H as primers. PPTs and tRNA primers are then removed by RNase H. The 3' and 5' ssDNA PBS regions hybridize to form a circular dsDNA intermediate. Strand displacement synthesis by RT to the PBS and PPT ends produces a blunt ended, linear dsDNA copy of the viral genome that includes long terminal repeats (LTRs) at both ends (By similarity). Integrase catalyzes viral DNA integration into the host chromosome, by performing a series of DNA cutting and joining reactions. This enzyme activity takes place after virion entry into a cell and reverse transcription of the RNA genome in dsDNA. The first step in the integration process is 3' processing. This step requires a complex comprising the viral genome, matrix protein, Vpr and integrase. This complex is called the pre-integration complex (PIC). The integrase protein removes 2 nucleotides from each 3' end of the viral DNA, leaving recessed CA OH's at the 3' ends. In the second step, the PIC enters cell nucleus. This process is mediated through integrase and Vpr proteins, and allows the virus to infect a non dividing cell. This ability to enter the nucleus is specific of lentiviruses, other retroviruses cannot and rely on cell division to access cell chromosomes. In the third step, termed strand transfer, the integrase protein joins the previously processed 3' ends to the 5' ends of strands of target cellular DNA at the site of integration. The 5'-ends are produced by integrase-catalyzed staggered cuts, 5 bp apart. A Y-shaped, gapped, recombination intermediate results, with the 5'-ends of the viral DNA strands and the 3' ends of target DNA strands remaining unjoined, flanking a gap of 5 bp. The last step is viral DNA integration into host chromosome. This involves host DNA repair synthesis in which the 5 bp gaps between the unjoined strands are filled in and then ligated. Since this process occurs at both cuts flanking the HIV genome, a 5 bp duplication of host DNA is produced at the ends of HIV-1 integration. Alternatively, Integrase may catalyze the excision of viral DNA just after strand transfer, this is termed disintegration (By similarity).
	~~<div style="background-color:#fffaf0;">~~
	~~== Publication Abstract from PubMed ==~~
	The emergence of resistance to existing classes of antiretroviral drugs necessitates finding new HIV-1 targets for drug discovery. The viral CA (capsid) protein represents one such potential new target. CA is sufficient to form mature HIV-1 capsids in vitro and extensive structure-function and mutational analyses of CA have shown that the proper assembly, morphology and stability of the mature capsid core are essential for the infectivity of HIV-1 virions. Here we describe the development of an in vitro capsid assembly assay based on association of CA-NC subunits on immobilized oligonucleotides. This assay was used to screen a compound library, yielding several different families of compounds that inhibited capsid assembly. Optimization of two chemical series, termed the benzodiazepines (BD) and the benzimidazoles (BM) resulted in compounds with potent antiviral activity against wild type and drug-resistant HIV-1. NMR spectroscopic and X-ray crystallographic analyses showed that both series of inhibitors bound to the N-terminal domain of CA. These inhibitors induce the formation of a pocket that overlaps with the binding site for the previously reported CAP inhibitors, but is expanded significantly by these new, more potent CA inhibitors. Virus release and EM studies showed that the BD compounds prevented virion release, whereas the BM compounds inhibited formation of the mature capsid. Passage of virus in the presence of the inhibitors selected for resistance mutations that mapped to highly conserved residues surrounding the inhibitor binding pocket, but also to the C-terminal domain of CA. The resistance mutations selected by the two series differed, consistent with differences in their interactions within the pocket, and most also impaired virus replicative capacity. Resistance mutations had two modes of action, either directly impacting inhibitor binding affinity or apparently increasing the overall stability of the viral capsid without affecting inhibitor binding. These studies demonstrate that CA is a viable antiviral target and demonstrate that inhibitors that bind within the same site on CA can have distinct binding modes and mechanisms of action.

	Distinct effects of two HIV-1 capsid assembly inhibitor families that bind the same site within the N-terminal domain of the viral CA protein.,Lemke CT, Titolo S, von Schwedler U, Goudreau N, Mercier JF, Wardrop E, Faucher AM, Coulombe R, Banik SS, Fader L, Gagnon A, Kawai SH, Rancourt J, Tremblay M, Yoakim C, Simoneau B, Archambault J, Sundquist WI, Mason SW J Virol. 2012 Apr 11. PMID:22496222<ref>PMID:22496222</ref>

	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~
	~~</div>~~
	~~<div class="pdbe-citations 4e91" style="background-color:#fffaf0;"></div>~~
	~~== References ==~~
	~~<references/>~~
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 06:58, 28 September 2022

2022-09-28T06:58:05Z

← Older revision		Revision as of 06:58, 28 September 2022
Line 1:		Line 1:

	==Crystal Structure of the N-Terminal Domain of HIV-1 Capsid in Complex With Inhibitor BD3==		==Crystal Structure of the N-Terminal Domain of HIV-1 Capsid in Complex With Inhibitor BD3==
	<StructureSection load='4e91' size='340' side='right' caption='[[4e91]], [[Resolution\|resolution]] 1.70Å' scene=''>		<StructureSection load='4e91' size='340' side='right'caption='[[4e91]], [[Resolution\|resolution]] 1.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4e91]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~9hiv1 9hiv1~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E91 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4E91 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4e91]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E91 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4E91 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0OE:4-{2-[5-(3-CHLOROPHENYL)-1H-PYRAZOL-4-YL]-1-[3-(1H-IMIDAZOL-1-YL)PROPYL]-1H-BENZIMIDAZOL-5-YL}BENZOIC+ACID'>0OE</scene>, <scene name='pdbligand=0OF:(3S)-1-ETHYL-3-[3-HYDROXY-5-(PYRIDIN-3-YL)PHENYL]-5-PHENYL-7-(TRIFLUOROMETHYL)-1H-1,5-BENZODIAZEPINE-2,4(3H,5H)-DIONE'>0OF</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>~~</td></tr>~~		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0OE:4-{2-[5-(3-CHLOROPHENYL)-1H-PYRAZOL-4-YL]-1-[3-(1H-IMIDAZOL-1-YL)PROPYL]-1H-BENZIMIDAZOL-5-YL}BENZOIC+ACID'>0OE</scene>, <scene name='pdbligand=0OF:(3S)-1-ETHYL-3-[3-HYDROXY-5-(PYRIDIN-3-YL)PHENYL]-5-PHENYL-7-(TRIFLUOROMETHYL)-1H-1,5-BENZODIAZEPINE-2,4(3H,5H)-DIONE'>0OF</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4e92\|4e92]]</td></tr>~~		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4e91 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e91 OCA], [https://pdbe.org/4e91 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4e91 RCSB], [https://www.ebi.ac.uk/pdbsum/4e91 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4e91 ProSAT]</span></td></tr>
	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">gag ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 9HIV1])~~</td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4e91 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e91 OCA], [~~http~~://pdbe.org/4e91 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4e91 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4e91 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4e91 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[[~~http~~://www.uniprot.org/uniprot/~~Q79791_9HIV1 Q79791_9HIV1~~]] Capsid protein p24 forms the conical core ~~of the virus~~ that encapsulates the genomic RNA-nucleocapsid complex (By similarity).~~[SAAS:SAAS000071_004_008806]~~ Nucleocapsid protein p7 encapsulates and protects viral dimeric unspliced (genomic) RNA. Binds these RNAs through its zinc fingers (By similarity).~~[SAAS:SAAS000071_004_011858]~~		[[https://www.uniprot.org/uniprot/POL_HV1N5 POL_HV1N5]] Gag-Pol polyprotein and Gag polyprotein may regulate their own translation, by the binding genomic RNA in the 5'-UTR. At low concentration, Gag-Pol and Gag would promote translation, whereas at high concentration, the polyproteins encapsidate genomic RNA and then shutt off translation (By similarity). Matrix protein p17 has two main functions: in infected cell, it targets Gag and Gag-pol polyproteins to the plasma membrane via a multipartite membrane-binding signal, that includes its myristoylated N-terminus. The second function is to play a role in nuclear localization of the viral genome at the very start of cell infection. Matrix protein is the part of the pre-integration complex. It binds in the cytoplasm the human BAF protein which prevent autointegration of the viral genome, and might be included in virions at the ration of zero to 3 BAF dimer per virion. The myristoylation signal and the NLS thus exert conflicting influences its subcellular localization. The key regulation of these motifs might be phosphorylation of a portion of MA molecules on the C-terminal tyrosine at the time of virus maturation, by virion-associated cellular tyrosine kinase. Implicated in the release from host cell mediated by Vpu (By similarity). Capsid protein p24 forms the conical core that encapsulates the genomic RNA-nucleocapsid complex in the virion. Most core are conical, with only 7% tubular. The core is constituted by capsid protein hexamer subunits. The core is disassembled soon after virion entry. Interaction with human PPIA/CYPA protects the virus from restriction by human TRIM5-alpha and from an unknown antiviral activity in human cells. This capsid restriction by TRIM5 is one of the factors which restricts HIV-1 to the human species (By similarity). Nucleocapsid protein p7 encapsulates and protects viral dimeric unspliced (genomic) RNA. Binds these RNAs through its zinc fingers. Facilitates rearangement of nucleic acid secondary structure during retrotranscription of genomic RNA. This capability is referred to as nucleic acid chaperone activity (By similarity). The aspartyl protease mediates proteolytic cleavages of Gag and Gag-Pol polyproteins during or shortly after the release of the virion from the plasma membrane. Cleavages take place as an ordered, step-wise cascade to yield mature proteins. This process is called maturation. Displays maximal activity during the budding process just prior to particle release from the cell. Also cleaves Nef and Vif, probably concomitantly with viral structural proteins on maturation of virus particles (By similarity). Reverse transcriptase/ribonuclease H (RT) is a multifunctional enzyme that converts the viral RNA genome into dsDNA in the cytoplasm, shortly after virus entry into the cell. This enzyme displays a DNA polymerase activity that can copy either DNA or RNA templates, and a ribonuclease H (RNase H) activity that cleaves the RNA strand of RNA-DNA heteroduplexes in a partially processive 3' to 5' endonucleasic mode. Conversion of viral genomic RNA into dsDNA requires many steps. A tRNA(3)-Lys binds to the primer-binding site (PBS) situated at the 5'-end of the viral RNA. RT uses the 3' end of the tRNA primer to perform a short round of RNA-dependent minus-strand DNA synthesis. The reading proceeds through the U5 region and ends after the repeated (R) region which is present at both ends of viral RNA. The portion of the RNA-DNA heteroduplex is digested by the RNase H, resulting in a ssDNA product attached to the tRNA primer. This ssDNA/tRNA hybridizes with the identical R region situated at the 3' end of viral RNA. This template exchange, known as minus-strand DNA strong stop transfer, can be either intra- or intermolecular. RT uses the 3' end of this newly synthesized short ssDNA to perform the RNA-dependent minus-strand DNA synthesis of the whole template. RNase H digests the RNA template except for two polypurine tracts (PPTs) situated at the 5'-end and near the center of the genome. It is not clear if both polymerase and RNase H activities are simultaneous. RNase H probably can proceed both in a polymerase-dependent (RNA cut into small fragments by the same RT performing DNA synthesis) and a polymerase-independent mode (cleavage of remaining RNA fragments by free RTs). Secondly, RT performs DNA-directed plus-strand DNA synthesis using the PPTs that have not been removed by RNase H as primers. PPTs and tRNA primers are then removed by RNase H. The 3' and 5' ssDNA PBS regions hybridize to form a circular dsDNA intermediate. Strand displacement synthesis by RT to the PBS and PPT ends produces a blunt ended, linear dsDNA copy of the viral genome that includes long terminal repeats (LTRs) at both ends (By similarity). Integrase catalyzes viral DNA integration into the host chromosome, by performing a series of DNA cutting and joining reactions. This enzyme activity takes place after virion entry into a cell and reverse transcription of the RNA genome in dsDNA. The first step in the integration process is 3' processing. This step requires a complex comprising the viral genome, matrix protein, Vpr and integrase. This complex is called the pre-integration complex (PIC). The integrase protein removes 2 nucleotides from each 3' end of the viral DNA, leaving recessed CA OH's at the 3' ends. In the second step, the PIC enters cell nucleus. This process is mediated through integrase and Vpr proteins, and allows the virus to infect a non dividing cell. This ability to enter the nucleus is specific of lentiviruses, other retroviruses cannot and rely on cell division to access cell chromosomes. In the third step, termed strand transfer, the integrase protein joins the previously processed 3' ends to the 5' ends of strands of target cellular DNA at the site of integration. The 5'-ends are produced by integrase-catalyzed staggered cuts, 5 bp apart. A Y-shaped, gapped, recombination intermediate results, with the 5'-ends of the viral DNA strands and the 3' ends of target DNA strands remaining unjoined, flanking a gap of 5 bp. The last step is viral DNA integration into host chromosome. This involves host DNA repair synthesis in which the 5 bp gaps between the unjoined strands are filled in and then ligated. Since this process occurs at both cuts flanking the HIV genome, a 5 bp duplication of host DNA is produced at the ends of HIV-1 integration. Alternatively, Integrase may catalyze the excision of viral DNA just after strand transfer, this is termed disintegration (By similarity).
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 20:		Line 18:
	</div>		</div>
	<div class="pdbe-citations 4e91" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4e91" style="background-color:#fffaf0;"></div>

	~~==See Also==~~
	*[[Gag polyprotein\|Gag polyprotein]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Lemke, C T~~]]		[[Category: Human immunodeficiency virus 1]]
	[[Category: ~~Structural protein~~]]		[[Category: Large Structures]]
	[[Category: ~~Structural protein capsid]]~~		[[Category: Lemke CT]]
	~~[[Category: Structural protein-inhibitor complex~~]]

OCA at 09:31, 5 August 2016

2016-08-05T09:31:07Z

← Older revision		Revision as of 09:31, 5 August 2016
Line 1:		Line 1:

	==Crystal Structure of the N-Terminal Domain of HIV-1 Capsid in Complex With Inhibitor BD3==		==Crystal Structure of the N-Terminal Domain of HIV-1 Capsid in Complex With Inhibitor BD3==
	<StructureSection load='4e91' size='340' side='right' caption='[[4e91]], [[Resolution\|resolution]] 1.70Å' scene=''>		<StructureSection load='4e91' size='340' side='right' caption='[[4e91]], [[Resolution\|resolution]] 1.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4e91]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Human_immunodeficiency_virus_1 Human immunodeficiency virus 1~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E91 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4E91 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4e91]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/9hiv1 9hiv1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E91 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4E91 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0OE:4-{2-[5-(3-CHLOROPHENYL)-1H-PYRAZOL-4-YL]-1-[3-(1H-IMIDAZOL-1-YL)PROPYL]-1H-BENZIMIDAZOL-5-YL}BENZOIC+ACID'>0OE</scene>, <scene name='pdbligand=0OF:(3S)-1-ETHYL-3-[3-HYDROXY-5-(PYRIDIN-3-YL)PHENYL]-5-PHENYL-7-(TRIFLUOROMETHYL)-1H-1,5-BENZODIAZEPINE-2,4(3H,5H)-DIONE'>0OF</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0OE:4-{2-[5-(3-CHLOROPHENYL)-1H-PYRAZOL-4-YL]-1-[3-(1H-IMIDAZOL-1-YL)PROPYL]-1H-BENZIMIDAZOL-5-YL}BENZOIC+ACID'>0OE</scene>, <scene name='pdbligand=0OF:(3S)-1-ETHYL-3-[3-HYDROXY-5-(PYRIDIN-3-YL)PHENYL]-5-PHENYL-7-(TRIFLUOROMETHYL)-1H-1,5-BENZODIAZEPINE-2,4(3H,5H)-DIONE'>0OF</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4e92\|4e92]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4e92\|4e92]]</td></tr>
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">gag ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 ~~Human immunodeficiency virus 1~~])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">gag ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 9HIV1])</td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4e91 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e91 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4e91 RCSB], [http://www.ebi.ac.uk/pdbsum/4e91 PDBsum]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4e91 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e91 OCA], [http://pdbe.org/4e91 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4e91 RCSB], [http://www.ebi.ac.uk/pdbsum/4e91 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4e91 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 19:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
			<div class="pdbe-citations 4e91" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 25:		Line 27:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	~~[[Category: Human immunodeficiency virus 1]]~~
	[[Category: Lemke, C T]]		[[Category: Lemke, C T]]
	[[Category: Structural protein]]		[[Category: Structural protein]]
	[[Category: Structural protein capsid]]		[[Category: Structural protein capsid]]
	[[Category: Structural protein-inhibitor complex]]		[[Category: Structural protein-inhibitor complex]]

OCA at 17:41, 25 December 2014

2014-12-25T17:41:16Z

← Older revision		Revision as of 17:41, 25 December 2014
Line 1:		Line 1:
	~~{{STRUCTURE_4e91\| PDB=4e91 \| SCENE= }}~~		==Crystal Structure of the N-Terminal Domain of HIV-1 Capsid in Complex With Inhibitor BD3==
	===Crystal Structure of the N-Terminal Domain of HIV-1 Capsid in Complex With Inhibitor BD3===		<StructureSection load='4e91' size='340' side='right' caption='[[4e91]], [[Resolution\|resolution]] 1.70Å' scene=''>
	{~~{ABSTRACT_PUBMED_22496222}~~}		== Structural highlights ==
			<table><tr><td colspan='2'>[[4e91]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E91 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4E91 FirstGlance]. <br>
			</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0OE:4-{2-[5-(3-CHLOROPHENYL)-1H-PYRAZOL-4-YL]-1-[3-(1H-IMIDAZOL-1-YL)PROPYL]-1H-BENZIMIDAZOL-5-YL}BENZOIC+ACID'>0OE</scene>, <scene name='pdbligand=0OF:(3S)-1-ETHYL-3-[3-HYDROXY-5-(PYRIDIN-3-YL)PHENYL]-5-PHENYL-7-(TRIFLUOROMETHYL)-1H-1,5-BENZODIAZEPINE-2,4(3H,5H)-DIONE'>0OF</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
			<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4e92\|4e92]]</td></tr>
			<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">gag ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 Human immunodeficiency virus 1])</td></tr>
			<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4e91 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e91 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4e91 RCSB], [http://www.ebi.ac.uk/pdbsum/4e91 PDBsum]</span></td></tr>
			</table>
			== Function ==
			[[http://www.uniprot.org/uniprot/Q79791_9HIV1 Q79791_9HIV1]] Capsid protein p24 forms the conical core of the virus that encapsulates the genomic RNA-nucleocapsid complex (By similarity).[SAAS:SAAS000071_004_008806] Nucleocapsid protein p7 encapsulates and protects viral dimeric unspliced (genomic) RNA. Binds these RNAs through its zinc fingers (By similarity).[SAAS:SAAS000071_004_011858]
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			The emergence of resistance to existing classes of antiretroviral drugs necessitates finding new HIV-1 targets for drug discovery. The viral CA (capsid) protein represents one such potential new target. CA is sufficient to form mature HIV-1 capsids in vitro and extensive structure-function and mutational analyses of CA have shown that the proper assembly, morphology and stability of the mature capsid core are essential for the infectivity of HIV-1 virions. Here we describe the development of an in vitro capsid assembly assay based on association of CA-NC subunits on immobilized oligonucleotides. This assay was used to screen a compound library, yielding several different families of compounds that inhibited capsid assembly. Optimization of two chemical series, termed the benzodiazepines (BD) and the benzimidazoles (BM) resulted in compounds with potent antiviral activity against wild type and drug-resistant HIV-1. NMR spectroscopic and X-ray crystallographic analyses showed that both series of inhibitors bound to the N-terminal domain of CA. These inhibitors induce the formation of a pocket that overlaps with the binding site for the previously reported CAP inhibitors, but is expanded significantly by these new, more potent CA inhibitors. Virus release and EM studies showed that the BD compounds prevented virion release, whereas the BM compounds inhibited formation of the mature capsid. Passage of virus in the presence of the inhibitors selected for resistance mutations that mapped to highly conserved residues surrounding the inhibitor binding pocket, but also to the C-terminal domain of CA. The resistance mutations selected by the two series differed, consistent with differences in their interactions within the pocket, and most also impaired virus replicative capacity. Resistance mutations had two modes of action, either directly impacting inhibitor binding affinity or apparently increasing the overall stability of the viral capsid without affecting inhibitor binding. These studies demonstrate that CA is a viable antiviral target and demonstrate that inhibitors that bind within the same site on CA can have distinct binding modes and mechanisms of action.

	~~==Function==~~		Distinct effects of two HIV-1 capsid assembly inhibitor families that bind the same site within the N-terminal domain of the viral CA protein.,Lemke CT, Titolo S, von Schwedler U, Goudreau N, Mercier JF, Wardrop E, Faucher AM, Coulombe R, Banik SS, Fader L, Gagnon A, Kawai SH, Rancourt J, Tremblay M, Yoakim C, Simoneau B, Archambault J, Sundquist WI, Mason SW J Virol. 2012 Apr 11. PMID:22496222<ref>PMID:22496222</ref>
	~~[[http://www.uniprot.org/uniprot/Q79791_9HIV1 Q79791_9HIV1]] Capsid protein p24 forms the conical core~~ of the ~~virus that encapsulates~~ the ~~genomic RNA~~-~~nucleocapsid complex (By similarity)~~.~~[SAAS:SAAS000071_004_008806] Nucleocapsid protein p7 encapsulates and protects viral dimeric unspliced (genomic) RNA~~. ~~Binds these RNAs through its zinc fingers (By similarity)~~.~~[SAAS~~:~~SAAS000071_004_011858]~~

	~~==About this Structure==~~		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	~~[[4e91]] is~~ a ~~2 chain structure with sequence from [http://en~~.~~wikipedia~~.~~org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]~~. ~~Full crystallographic information is available from [http:/~~/~~oca.weizmann.ac.il/oca-bin/ocashort?id=4E91 OCA].~~		</div>

	==~~Reference~~==		==See Also==
	~~<ref group~~=~~"xtra">PMID:022496222</ref>~~<references ~~group="xtra"~~/><~~references~~/>		*[[Gag polyprotein\|Gag polyprotein]]
			== References ==
			<references/>
			__TOC__
			</StructureSection>
	[[Category: Human immunodeficiency virus 1]]		[[Category: Human immunodeficiency virus 1]]
	[[Category: Lemke, C T.]]		[[Category: Lemke, C T]]
	[[Category: Structural protein]]		[[Category: Structural protein]]
	[[Category: Structural protein capsid]]		[[Category: Structural protein capsid]]
	[[Category: Structural protein-inhibitor complex]]		[[Category: Structural protein-inhibitor complex]]

OCA at 21:09, 19 June 2013

2013-06-19T21:09:05Z

← Older revision		Revision as of 21:09, 19 June 2013
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	~~[[Image:4e91.png\|left\|200px]]~~

	~~<!--~~
	~~The line below this paragraph, containing "STRUCTURE_4e91", creates the "Structure Box" on the page.~~
	~~You may change the PDB parameter (which sets the PDB file loaded into the applet)~~
	~~or the SCENE parameter (which sets the initial scene displayed when the page is loaded),~~
	~~or leave the SCENE parameter empty for the default display.~~
	~~-->~~
	{{STRUCTURE_4e91\| PDB=4e91 \| SCENE= }}		{{STRUCTURE_4e91\| PDB=4e91 \| SCENE= }}

	===Crystal Structure of the N-Terminal Domain of HIV-1 Capsid in Complex With Inhibitor BD3===		===Crystal Structure of the N-Terminal Domain of HIV-1 Capsid in Complex With Inhibitor BD3===
			{{ABSTRACT_PUBMED_22496222}}

			==Function==
	~~<!--~~		[[http://www.uniprot.org/uniprot/Q79791_9HIV1 Q79791_9HIV1]] Capsid protein p24 forms the conical core of the virus that encapsulates the genomic RNA-nucleocapsid complex (By similarity).[SAAS:SAAS000071_004_008806] Nucleocapsid protein p7 encapsulates and protects viral dimeric unspliced (genomic) RNA. Binds these RNAs through its zinc fingers (By similarity).[SAAS:SAAS000071_004_011858]
	~~The line below this paragraph, {{ABSTRACT_PUBMED_22496222}}, adds the Publication Abstract to the page~~
	~~(as it appears on PubMed at~~ http://www.~~pubmed~~.~~gov~~)~~, where 22496222 is the PubMed ID number~~.
	~~-->~~
	~~{{ABSTRACT_PUBMED_22496222}}~~

	==About this Structure==		==About this Structure==
Line 22:		Line 10:

	==Reference==		==Reference==
	<ref group="xtra">PMID:022496222</ref><references group="xtra"/>		<ref group="xtra">PMID:022496222</ref><references group="xtra"/><references/>
	[[Category: Human immunodeficiency virus 1]]		[[Category: Human immunodeficiency virus 1]]
	[[Category: Lemke, C T.]]		[[Category: Lemke, C T.]]

OCA at 06:36, 6 June 2012

2012-06-06T06:36:19Z

← Older revision		Revision as of 06:36, 6 June 2012
Line 1:		Line 1:
	[[Image:4e91.~~jpg~~\|left\|200px]]		[[Image:4e91.png\|left\|200px]]

	<!--		<!--

OCA at 09:14, 25 April 2012

2012-04-25T09:14:05Z

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
+[[Image:4e91.jpg|left|200px]]
-The entry 4e91 is ON HOLD
+<!--
-Authors: Lemke, C.T.
+===Crystal Structure of the N-Terminal Domain of HIV-1 Capsid in Complex With Inhibitor BD3===
-Description: Crystal Structure of the N-Terminal Domain of HIV-1 Capsid in Complex With Inhibitor BD3

OCA: Protected "4e91" [edit=sysop:move=sysop]

2012-03-28T07:25:08Z

Protected "4e91" [edit=sysop:move=sysop]

← Older revision	Revision as of 07:25, 28 March 2012
(No difference)

OCA: New page: '''Unreleased structure''' The entry 4e91 is ON HOLD Authors: Lemke, C.T. Description: Crystal Structure of the N-Terminal Domain of HIV-1 Capsid in Complex With Inhibitor BD3

2012-03-28T07:25:07Z

New page: '''Unreleased structure''' The entry 4e91 is ON HOLD Authors: Lemke, C.T. Description: Crystal Structure of the N-Terminal Domain of HIV-1 Capsid in Complex With Inhibitor BD3

New page

'''Unreleased structure'''

The entry 4e91 is ON HOLD

Authors: Lemke, C.T.

Description: Crystal Structure of the N-Terminal Domain of HIV-1 Capsid in Complex With Inhibitor BD3