Proteopedia - User contributions [en]

User:Orly Dym/Sandbox

2010-02-21T09:11:31Z

Orly Dym:

User:Orly Dym/Sandbox

2010-02-21T09:08:09Z

Orly Dym:

User:Orly Dym/Sandbox

2010-02-21T09:07:33Z

Orly Dym:

tehwwe rwe rwfmsf SERSMF.DFMD [[2rci]]

<applet load='2rci' size='300' frame='true' align='right' caption='Insert caption here' />
<scene name='User:Orly_Dym/Sandbox/X/1'>TextToBeDisplayed</scene>

[[Image:1KT0_Domain12_Elc.png|thumb|Electron density of HLA-A2 peptide-binding groove showing density of mixed peptides. Figure 6b from [[1hla#Reference | Bjorkman et al., Nature 329:506]], used with permission of Dr. Pamela Bjorkman.]]

User:Orly Dym/Sandbox

2010-02-21T09:06:14Z

Orly Dym:

User:Orly Dym/Sandbox

2010-02-21T09:05:06Z

Orly Dym:

User:Orly Dym/Sandbox

2010-02-21T09:04:33Z

Orly Dym:

User:Orly Dym/Sandbox

2010-02-21T09:00:11Z

Orly Dym:

File:1KT0 Domain12 Elc.png

2010-02-21T08:58:47Z

Orly Dym:

User:Orly Dym/Sandbox

2010-02-21T08:56:43Z

Orly Dym:

tehwwe rwe rwfmsf SERSMF.DFMD [[2rci]]

<applet load='2rci' size='300' frame='true' align='right' caption='Insert caption here' />
<scene name='User:Orly_Dym/Sandbox/X/1'>TextToBeDisplayed</scene>

User:Orly Dym/Sandbox

2010-02-21T08:44:57Z

Orly Dym:

tehwwe rwe rwfmsf SERSMF.DFMD [[2rci]]

<applet load='2rci' size='300' frame='true' align='right' caption='Insert caption here' />

User:Orly Dym/Sandbox

2010-02-21T08:44:19Z

Orly Dym:

tehwwe rwe rwfmsf SERSMF.DFMD

<applet load='2rci' size='300' frame='true' align='right' caption='Insert caption here' />

User:Orly Dym/Sandbox

2010-02-21T08:43:38Z

Orly Dym: New page: tehwwe rwe rwfmsf SERSMF.DFMD <applet load='3kih' size='300' frame='true' align='right' caption='Insert caption here' />

tehwwe rwe rwfmsf SERSMF.DFMD

<applet load='3kih' size='300' frame='true' align='right' caption='Insert caption here' />

User:Orly Dym

2008-04-13T10:01:42Z

Orly Dym: New page: Orly Dym

Orly Dym

File:AzI.pdb

2008-04-02T13:07:36Z

Orly Dym:

Sandbox 12

2008-04-02T12:14:59Z

Orly Dym:

<applet load="2uv8" size="300" frame="true" align="right" />

==This is a placeholder==
This is a placeholder text to help you get started in
placing a Jmol applet on your page. At any time, click
"Show Preview" at the bottom of this page to see how it goes.

Replace the PDB id after the load=" to load and display
another structure.

Sandbox 12

2008-04-02T12:14:14Z

Orly Dym:

<applet load="2ug8" size="300" frame="true" align="right" />

==This is a placeholder==
This is a placeholder text to help you get started in
placing a Jmol applet on your page. At any time, click
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Replace the PDB id after the load=" to load and display
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Sandbox 12

2008-04-02T12:11:45Z

Orly Dym:

<applet load="1UG3" size="300" frame="true" align="right" />

==This is a placeholder==
This is a placeholder text to help you get started in
placing a Jmol applet on your page. At any time, click
"Show Preview" at the bottom of this page to see how it goes.

Replace the PDB id after the load=" to load and display
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Sandbox 12

2008-04-02T12:11:09Z

Orly Dym: New page: <applet load="2ug8" size="300" frame="true" align="right" /> ==This is a placeholder== This is a placeholder text to help you get started in placing a Jmol applet on your page. At any ti...

Antizyme Inhibitor

2008-03-25T11:35:08Z

Orly Dym:

<applet load="3BTN.pdb" size="550" color="white" frame="true" align="right" spinBox="true"
caption="AzI, unpublished structure" />

Antizyme inhibitor (AzI) regulates cellular polyamine homeostasis by binding to the polyamine-induced protein, Antizyme (Az), with greater affinity than ODC. AzI is highly homologous to ornithine decarboxylase (ODC), but is not enzymatically active . In order to understand these specific characteristics of AzI and its differences from ODC, we determined the 3D structure of mouse AzI to 2.05Å resolution. Both AzI and ODC crystallize as a
<scene name='3btn/Azi/1'>dimer</scene> (one monomer in blue and the other in green).
However, fewer interactions at the dimer
<scene name='3btn/Interface/2'>interface</scene>, a smaller buried surface area, and lack of symmetry of the interactions between residues from the two monomers in the AzI structure suggest that this dimeric structure is non-physiological. In addition, the absence of residues and interactions required for
<scene name='3btn/Plp/1'>PLP</scene>
binding suggest that AzI does not bind PLP. A comparison to the <scene name='3btn/Plp/1'>PLP binding site of ODC</scene> revealed that AzI lacks the residues participating in PLP binding. Biochemical studies confirmed the lack of PLP binding and revealed that AzI exists as a monomer in solution while ODC is dimeric. Our findings that AzI exists as a monomer and its inability to bind PLP provide two independent explanations for its lack of enzymatic activity, and suggest the basis for its enhanced affinity towards Az.

Antizyme Inhibitor

2008-02-21T13:19:18Z

Orly Dym:

<applet load="3BTN.pdb" size="550" color="white" frame="true" align="right" spinBox="true"
caption="AzI, unpublished structure" />

Antizyme inhibitor (AzI) regulates cellular polyamine homeostasis by binding to the polyamine-induced protein, Antizyme (Az), with greater affinity than ODC. AzI is highly homologous to ornithine decarboxylase (ODC), but is not enzymatically active . In order to understand these specific characteristics of AzI and its differences from ODC, we determined the 3D structure of mouse AzI to 2.05Å resolution. Both AzI and ODC crystallize as a
<scene name='3btn/Azi/1'>dimer</scene> (one monomer in red and the other in green).
However, fewer interactions at the dimer
<scene name='3btn/Interface/2'>interface</scene>, a smaller buried surface area, and lack of symmetry of the interactions between residues from the two monomers in the AzI structure suggest that this dimeric structure is non-physiological. In addition, the absence of residues and interactions required for
<scene name='3btn/Plp/1'>PLP</scene>
binding suggest that AzI does not bind PLP. A comparison to the <scene name='3btn/Plp/1'>PLP binding site of ODC</scene> revealed that AzI lacks the residues participating in PLP binding. Biochemical studies confirmed the lack of PLP binding and revealed that AzI exists as a monomer in solution while ODC is dimeric. Our findings that AzI exists as a monomer and its inability to bind PLP provide two independent explanations for its lack of enzymatic activity, and suggest the basis for its enhanced affinity towards Az.

Antizyme Inhibitor

2008-02-21T13:17:46Z

Orly Dym:

<applet load="3BTN.pdb" size="550" color="white" frame="true" align="right" spinBox="true"
caption="AzI, unpublished structure" />

Antizyme inhibitor (AzI) regulates cellular polyamine homeostasis by binding to the polyamine-induced protein, Antizyme (Az), with greater affinity than ODC. AzI is highly homologous to ornithine decarboxylase (ODC), but is not enzymatically active . In order to understand these specific characteristics of AzI and its differences from ODC, we determined the 3D structure of mouse AzI to 2.05Å resolution. Both AzI and ODC crystallize as a
<scene name='3btn/Azi/1'>dimer</scene> (one monomer in red and the other in green).
However, fewer interactions at the dimer
<scene name='3btn/Interface/2'>interface</scene>, a smaller buried surface area, and lack of symmetry of the interactions between residues from the two monomers in the AzI structure suggest that this dimeric structure is non-physiological. In addition, the absence of residues and interactions required for
<scene name='3btn/Plp/1'>PLP</scene>
binding suggest that AzI does not bind PLP. A comparison to the PLP binding site of ODC revealed that AzI lacks the residues participating in PLP binding. Biochemical studies confirmed the lack of PLP binding and revealed that AzI exists as a monomer in solution while ODC is dimeric. Our findings that AzI exists as a monomer and its inability to bind PLP provide two independent explanations for its lack of enzymatic activity, and suggest the basis for its enhanced affinity towards Az.

File:PLP3.pdb

2008-02-21T12:51:54Z

Orly Dym:

File:PLP1.pdb

2008-02-20T15:40:45Z

Orly Dym: PLP1

PLP1

File:PLP.pdb

2008-02-20T15:38:11Z

Orly Dym: uploaded a new version of "Image:PLP.pdb": PLP

File:PLP.pdb

2008-02-20T15:35:57Z

Orly Dym:

Antizyme Inhibitor

2008-02-20T14:51:45Z

Orly Dym: New page: <applet load="3BTN.pdb" size="550" color="white" frame="true" align="right" spinBox="true" caption="AzI, unpublished structure" /> Antizyme inhibitor (AzI) regulates cellular polyamine h...

<applet load="3BTN.pdb" size="550" color="white" frame="true" align="right" spinBox="true"
caption="AzI, unpublished structure" />

Antizyme inhibitor (AzI) regulates cellular polyamine homeostasis by binding to the polyamine-induced protein, Antizyme (Az), with greater affinity than ODC. AzI is highly homologous to ornithine decarboxylase (ODC), but is not enzymatically active . In order to understand these specific characteristics of AzI and its differences from ODC, we determined the 3D structure of mouse AzI to 2.05Å resolution. Both AzI and ODC crystallize as a
<scene name='3btn/Azi/1'>dimer</scene> (one monomer in red and the other in green).
However, fewer interactions at the dimer
<scene name='3btn/Interface/2'>interface</scene>, a smaller buried surface area, and lack of symmetry of the interactions between residues from the two monomers in the AzI structure suggest that this dimeric structure is non-physiological. In addition, the absence of residues and interactions required for
<scene name='3btn/Plp/1'>PLP</scene>
binding suggest that AzI does not bind PLP. Biochemical studies confirmed the lack of PLP binding and revealed that AzI exists as a monomer in solution while ODC is dimeric. Our findings that AzI exists as a monomer and its inability to bind PLP provide two independent explanations for its lack of enzymatic activity, and suggest the basis for its enhanced affinity towards Az.

File:3BTN.pdb

2008-02-20T12:16:37Z

Orly Dym:

File:AzI Final.pdb

2008-02-20T12:14:02Z

Orly Dym:

NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol

2007-10-29T10:18:30Z

Orly Dym:

== The crystal structure of NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol ==
NAD(P)H quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two electron reduction of quinones to hydroquinones utilizing [[NAD(P)H]] as an electron donor.
NQO1 is a homo-dimer that functions via a “ping pong” mechanism. NAD(P)H binds to NQO1, reduces the [[FAD]] co-factor and is then released, allowing the quinone substrate to bind the enzyme and to be reduced. The NAD(P)H and the quinone binding sites of NQO1 have a significant overlap, thus providing a molecular basis for this “ping pong” mechanism.
Certain coumarins, flavones and the reactive dye cibacron blue are competitive inhibitors of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin))[[Image:Figure3 copy.jpg|border|center|300px]], is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the electron transfer to FAD.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the tumor suppressor p53 and several other short-lived proteins including [[p73α]] and ornithine decarboxylase ([[ODC]]). NQO1 binds and stabilizes [[p53]], protecting p53 from ubiquitin-independent 20S proteasomal degradation. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.
<applet load="2F1O" size="500" color="white" frame="true" align="right" caption="2F1O" />
The crystal structure of human<scene name='Nqo1/Nqo1_1/2'>NQO1</scene> in complex with dicoumarol was determine at 2.75 Å resolution.
NQO1 is a physiological homodimer composed of two interlocked monomers. Each monomer is composed of two domains: a large catalytic domain with α/β fold with flavodoxin topology (residues 1-220) and a small C-terminal domain (residues 221-273). Two catalytic sites are formed and are present at the dimer interface. Two FAD molecules (red) are present; each one is bound to the catalytic domain of each monomer. The dicoumarol molecule (purple) is bound to each of the catalytic sites interacting with FAD and with residues from both monomer.The dicoumarol molecule is bound to each of the catalytic sites interacting with FAD and with residues from both monomers.
[[Image:NQO_Dic copy.jpg|border|center|300px]]
Structural comparison of the apo hNQO1 dimer (PDB accession code 1D4A in cyan) with hNQO1 in complex with dicoumarol(pink) reveals that structural changes associated with dicoumarol binding occur on several residues involving both monomers. The most prominent conformational changes that occur in the presence of dicoumarol involve Tyr 128 and Phe 232 that are present on the surface of the NQO1 catalytic pocket. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.

[[Image:Slide1.jpg|border|center|300px]]

===sna===

NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol

2007-10-29T08:29:45Z

Orly Dym:

== The crystal structure of NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol ==
NAD(P)H quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two electron reduction of quinones to hydroquinones utilizing [[NAD(P)H]] as an electron donor.
NQO1 is a homo-dimer that functions via a “ping pong” mechanism. NAD(P)H binds to NQO1, reduces the [[FAD]] co-factor and is then released, allowing the quinone substrate to bind the enzyme and to be reduced. The NAD(P)H and the quinone binding sites of NQO1 have a significant overlap, thus providing a molecular basis for this “ping pong” mechanism.
Certain coumarins, flavones and the reactive dye cibacron blue are competitive inhibitors of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin))[[Image:Figure3 copy.jpg|border|center|300px]], is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the electron transfer to FAD.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the tumor suppressor p53 and several other short-lived proteins including [[p73α]] and ornithine decarboxylase ([[ODC]]). NQO1 binds and stabilizes [[p53]], protecting p53 from ubiquitin-independent 20S proteasomal degradation. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.
<applet load="2F1O" size="500" color="white" frame="true" align="right" caption="2F1O" />
The crystal structure of human <scene name='Nqo1/Nqo2/1'>NQO1</scene> in complex with dicoumarol was determine at 2.75 Å resolution.
NQO1 is a physiological homodimer composed of two interlocked monomers. Each monomer is composed of two domains: a large catalytic domain with α/β fold with flavodoxin topology (residues 1-220) and a small C-terminal domain (residues 221-273). Two catalytic sites are formed and are present at the dimer interface. Two FAD molecules (red) are present; each one is bound to the catalytic domain of each monomer. The dicoumarol molecule (purple) is bound to each of the catalytic sites interacting with FAD and with residues from both monomer.The dicoumarol molecule is bound to each of the catalytic sites interacting with FAD and with residues from both monomers.
[[Image:NQO_Dic copy.jpg|border|center|300px]]
Structural comparison of the apo hNQO1 dimer (PDB accession code 1D4A in cyan) with hNQO1 in complex with dicoumarol(pink) reveals that structural changes associated with dicoumarol binding occur on several residues involving both monomers. The most prominent conformational changes that occur in the presence of dicoumarol involve Tyr 128 and Phe 232 that are present on the surface of the NQO1 catalytic pocket. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.

[[Image:Slide1.jpg|border|center|300px]]

===sna===

NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol

2007-10-29T08:13:51Z

Orly Dym:

== The crystal structure of NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol ==
NAD(P)H quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two electron reduction of quinones to hydroquinones utilizing [[NAD(P)H]] as an electron donor.
NQO1 is a homo-dimer that functions via a “ping pong” mechanism. NAD(P)H binds to NQO1, reduces the [[FAD]] co-factor and is then released, allowing the quinone substrate to bind the enzyme and to be reduced. The NAD(P)H and the quinone binding sites of NQO1 have a significant overlap, thus providing a molecular basis for this “ping pong” mechanism.
Certain coumarins, flavones and the reactive dye cibacron blue are competitive inhibitors of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin))[[Image:Figure3 copy.jpg|border|center|300px]], is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the electron transfer to FAD.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the tumor suppressor p53 and several other short-lived proteins including [[p73α]] and ornithine decarboxylase ([[ODC]]). NQO1 binds and stabilizes [[p53]], protecting p53 from ubiquitin-independent 20S proteasomal degradation. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.
<applet load="2F1O" size="500" color="white" frame="true" align="right" caption="2F1O" />
The crystal structure of human <scene name='Nqo1/Nqo2/1'>NQO1</scene>
in complex with dicoumarol was determine at 2.75 Å resolution.
NQO1 is a physiological homodimer composed of two interlocked monomers. Each monomer is composed of two domains: a large catalytic domain with α/β fold with flavodoxin topology (residues 1-220) and a small C-terminal domain (residues 221-273). Two catalytic sites are formed and are present at the dimer interface. Two FAD molecules (red) are present; each one is bound to the catalytic domain of each monomer. The dicoumarol molecule (purple) is bound to each of the catalytic sites interacting with FAD and with residues from both monomer.The dicoumarol molecule is bound to each of the catalytic sites interacting with FAD and with residues from both monomers.
[[Image:NQO_Dic copy.jpg|border|center|300px]]
Structural comparison of the apo hNQO1 dimer (PDB accession code 1D4A in cyan) with hNQO1 in complex with dicoumarol(pink) reveals that structural changes associated with dicoumarol binding occur on several residues involving both monomers. The most prominent conformational changes that occur in the presence of dicoumarol involve Tyr 128 and Phe 232 that are present on the surface of the NQO1 catalytic pocket. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.

[[Image:Slide1.jpg|border|center|300px]]

===sna===

NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol

2007-10-29T08:13:10Z

Orly Dym:

== The crystal structure of NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol ==
NAD(P)H quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two electron reduction of quinones to hydroquinones utilizing [[NAD(P)H]] as an electron donor.
NQO1 is a homo-dimer that functions via a “ping pong” mechanism. NAD(P)H binds to NQO1, reduces the [[FAD]] co-factor and is then released, allowing the quinone substrate to bind the enzyme and to be reduced. The NAD(P)H and the quinone binding sites of NQO1 have a significant overlap, thus providing a molecular basis for this “ping pong” mechanism.
Certain coumarins, flavones and the reactive dye cibacron blue are competitive inhibitors of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin))[[Image:Figure3 copy.jpg|border|center|300px]], is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the electron transfer to FAD.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the tumor suppressor p53 and several other short-lived proteins including [[p73α]] and ornithine decarboxylase ([[ODC]]). NQO1 binds and stabilizes [[p53]], protecting p53 from ubiquitin-independent 20S proteasomal degradation. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.
<applet load="2F1O" size="500" color="white" frame="true" align="right" caption="2F1O" />
The crystal structure of human <scene name='Nqo1/Nqo2/1'>TextToBeDisplayed</scene>
in complex with dicoumarol was determine at 2.75 Å resolution.
NQO1 is a physiological homodimer composed of two interlocked monomers. Each monomer is composed of two domains: a large catalytic domain with α/β fold with flavodoxin topology (residues 1-220) and a small C-terminal domain (residues 221-273). Two catalytic sites are formed and are present at the dimer interface. Two FAD molecules (red) are present; each one is bound to the catalytic domain of each monomer. The dicoumarol molecule (purple) is bound to each of the catalytic sites interacting with FAD and with residues from both monomer.The dicoumarol molecule is bound to each of the catalytic sites interacting with FAD and with residues from both monomers.
[[Image:NQO_Dic copy.jpg|border|center|300px]]
Structural comparison of the apo hNQO1 dimer (PDB accession code 1D4A in cyan) with hNQO1 in complex with dicoumarol(pink) reveals that structural changes associated with dicoumarol binding occur on several residues involving both monomers. The most prominent conformational changes that occur in the presence of dicoumarol involve Tyr 128 and Phe 232 that are present on the surface of the NQO1 catalytic pocket. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.

[[Image:Slide1.jpg|border|center|300px]]

===sna===

NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol

2007-10-29T06:35:19Z

Orly Dym:

== The crystal structure of NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol ==
NAD(P)H quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two electron reduction of quinones to hydroquinones utilizing [[NAD(P)H]] as an electron donor.
NQO1 is a homo-dimer that functions via a “ping pong” mechanism. NAD(P)H binds to NQO1, reduces the [[FAD]] co-factor and is then released, allowing the quinone substrate to bind the enzyme and to be reduced. The NAD(P)H and the quinone binding sites of NQO1 have a significant overlap, thus providing a molecular basis for this “ping pong” mechanism.
Certain coumarins, flavones and the reactive dye cibacron blue are competitive inhibitors of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin))[[Image:Figure3 copy.jpg|border|center|300px]], is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the electron transfer to FAD.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the tumor suppressor p53 and several other short-lived proteins including [[p73α]] and ornithine decarboxylase ([[ODC]]). NQO1 binds and stabilizes [[p53]], protecting p53 from ubiquitin-independent 20S proteasomal degradation. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.
<applet load="2F1O" script="2F1O/Starting_scene/1" size="500" color="white" frame="true" align="right" spinBox="true" caption="2F1O " />
The crystal structure of human <scene name='Nqo1/Nqo1_1/1'> NQO1</scene> in complex with dicoumarol was determine at 2.75 Å resolution.
NQO1 is a physiological homodimer composed of two interlocked monomers. Each monomer is composed of two domains: a large catalytic domain with α/β fold with flavodoxin topology (residues 1-220) and a small C-terminal domain (residues 221-273). Two catalytic sites are formed and are present at the dimer interface. Two FAD molecules (red) are present; each one is bound to the catalytic domain of each monomer. The dicoumarol molecule (purple) is bound to each of the catalytic sites interacting with FAD and with residues from both monomer.The dicoumarol molecule is bound to each of the catalytic sites interacting with FAD and with residues from both monomers.
[[Image:NQO_Dic copy.jpg|border|center|300px]]
Structural comparison of the apo hNQO1 dimer (PDB accession code 1D4A in cyan) with hNQO1 in complex with dicoumarol(pink) reveals that structural changes associated with dicoumarol binding occur on several residues involving both monomers. The most prominent conformational changes that occur in the presence of dicoumarol involve Tyr 128 and Phe 232 that are present on the surface of the NQO1 catalytic pocket. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.

[[Image:Slide1.jpg|border|center|300px]]

===sna===

NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol

2007-10-29T06:12:24Z

Orly Dym:

== The crystal structure of NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol ==
NAD(P)H quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two electron reduction of quinones to hydroquinones utilizing [[NAD(P)H]] as an electron donor.
NQO1 is a homo-dimer that functions via a “ping pong” mechanism. NAD(P)H binds to NQO1, reduces the [[FAD]] co-factor and is then released, allowing the quinone substrate to bind the enzyme and to be reduced. The NAD(P)H and the quinone binding sites of NQO1 have a significant overlap, thus providing a molecular basis for this “ping pong” mechanism.
Certain coumarins, flavones and the reactive dye cibacron blue are competitive inhibitors of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin))[[Image:Figure3 copy.jpg|border|center|300px]], is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the electron transfer to FAD.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the tumor suppressor p53 and several other short-lived proteins including [[p73α]] and ornithine decarboxylase ([[ODC]]). NQO1 binds and stabilizes [[p53]], protecting p53 from ubiquitin-independent 20S proteasomal degradation. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.

The crystal structure of human <scene name='Nqo1/Nqo1_1/1'> NQO1</scene> in complex with dicoumarol was determine at 2.75 Å resolution.
NQO1 is a physiological homodimer composed of two interlocked monomers. Each monomer is composed of two domains: a large catalytic domain with α/β fold with flavodoxin topology (residues 1-220) and a small C-terminal domain (residues 221-273). Two catalytic sites are formed and are present at the dimer interface. Two FAD molecules (red) are present; each one is bound to the catalytic domain of each monomer. The dicoumarol molecule (purple) is bound to each of the catalytic sites interacting with FAD and with residues from both monomer.The dicoumarol molecule is bound to each of the catalytic sites interacting with FAD and with residues from both monomers.
[[Image:NQO_Dic copy.jpg|border|center|300px]]
Structural comparison of the apo hNQO1 dimer (PDB accession code 1D4A in cyan) with hNQO1 in complex with dicoumarol(pink) reveals that structural changes associated with dicoumarol binding occur on several residues involving both monomers. The most prominent conformational changes that occur in the presence of dicoumarol involve Tyr 128 and Phe 232 that are present on the surface of the NQO1 catalytic pocket. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.

[[Image:Slide1.jpg|border|center|300px]]

===sna===

NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol

2007-10-29T06:11:41Z

Orly Dym:

== The crystal structure of NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol ==
NAD(P)H quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two electron reduction of quinones to hydroquinones utilizing [[NAD(P)H]] as an electron donor.
NQO1 is a homo-dimer that functions via a “ping pong” mechanism. NAD(P)H binds to NQO1, reduces the [[FAD]] co-factor and is then released, allowing the quinone substrate to bind the enzyme and to be reduced. The NAD(P)H and the quinone binding sites of NQO1 have a significant overlap, thus providing a molecular basis for this “ping pong” mechanism.
Certain coumarins, flavones and the reactive dye cibacron blue are competitive inhibitors of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin))[[Image:Figure3 copy.jpg|border|center|300px]], is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the electron transfer to FAD.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the tumor suppressor p53 and several other short-lived proteins including [[p73α]] and ornithine decarboxylase ([[ODC]]). NQO1 binds and stabilizes [[p53]], protecting p53 from ubiquitin-independent 20S proteasomal degradation. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.

The crystal structure of human Nqo1_1 <scene name='Nqo1/Nqo1_1/1'>TextToBeDisplayed</scene> in complex with dicoumarol was determine at 2.75 Å resolution.
NQO1 is a physiological homodimer composed of two interlocked monomers. Each monomer is composed of two domains: a large catalytic domain with α/β fold with flavodoxin topology (residues 1-220) and a small C-terminal domain (residues 221-273). Two catalytic sites are formed and are present at the dimer interface. Two FAD molecules (red) are present; each one is bound to the catalytic domain of each monomer. The dicoumarol molecule (purple) is bound to each of the catalytic sites interacting with FAD and with residues from both monomer.The dicoumarol molecule is bound to each of the catalytic sites interacting with FAD and with residues from both monomers.
[[Image:NQO_Dic copy.jpg|border|center|300px]]
Structural comparison of the apo hNQO1 dimer (PDB accession code 1D4A in cyan) with hNQO1 in complex with dicoumarol(pink) reveals that structural changes associated with dicoumarol binding occur on several residues involving both monomers. The most prominent conformational changes that occur in the presence of dicoumarol involve Tyr 128 and Phe 232 that are present on the surface of the NQO1 catalytic pocket. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.

[[Image:Slide1.jpg|border|center|300px]]

===sna===

NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol

2007-10-21T15:46:39Z

Orly Dym:

== The crystal structure of NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol ==
NAD(P)H quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two electron reduction of quinones to hydroquinones utilizing [[NAD(P)H]] as an electron donor.
NQO1 is a homo-dimer that functions via a “ping pong” mechanism. NAD(P)H binds to NQO1, reduces the [[FAD]] co-factor and is then released, allowing the quinone substrate to bind the enzyme and to be reduced. The NAD(P)H and the quinone binding sites of NQO1 have a significant overlap, thus providing a molecular basis for this “ping pong” mechanism.
Certain coumarins, flavones and the reactive dye cibacron blue are competitive inhibitors of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin))[[Image:Figure3 copy.jpg|border|center|300px]], is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the electron transfer to FAD.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the tumor suppressor p53 and several other short-lived proteins including [[p73α]] and ornithine decarboxylase ([[ODC]]). NQO1 binds and stabilizes [[p53]], protecting p53 from ubiquitin-independent 20S proteasomal degradation. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.

The crystal structure of human NQO1 in complex with dicoumarol was determine at 2.75 Å resolution.
NQO1 is a physiological homodimer composed of two interlocked monomers. Each monomer is composed of two domains: a large catalytic domain with α/β fold with flavodoxin topology (residues 1-220) and a small C-terminal domain (residues 221-273). Two catalytic sites are formed and are present at the dimer interface. Two FAD molecules (red) are present; each one is bound to the catalytic domain of each monomer. The dicoumarol molecule (purple) is bound to each of the catalytic sites interacting with FAD and with residues from both monomer.The dicoumarol molecule is bound to each of the catalytic sites interacting with FAD and with residues from both monomers.
[[Image:NQO_Dic copy.jpg|border|center|300px]]
Structural comparison of the apo hNQO1 dimer (PDB accession code 1D4A in cyan) with hNQO1 in complex with dicoumarol(pink) reveals that structural changes associated with dicoumarol binding occur on several residues involving both monomers. The most prominent conformational changes that occur in the presence of dicoumarol involve Tyr 128 and Phe 232 that are present on the surface of the NQO1 catalytic pocket. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.

[[Image:Slide1.jpg|border|center|300px]]

===sna===

NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol

2007-10-21T15:46:03Z

Orly Dym:

== The crystal structure of NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol ==
NAD(P)H quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two electron reduction of quinones to hydroquinones utilizing [[NAD(P)H]] as an electron donor.
NQO1 is a homo-dimer that functions via a “ping pong” mechanism. NAD(P)H binds to NQO1, reduces the [[FAD]] co-factor and is then released, allowing the quinone substrate to bind the enzyme and to be reduced. The NAD(P)H and the quinone binding sites of NQO1 have a significant overlap, thus providing a molecular basis for this “ping pong” mechanism.
Certain coumarins, flavones and the reactive dye cibacron blue are competitive inhibitors of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin))[[Image:Figure3 copy.jpg|border|center|300px]], is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the electron transfer to FAD.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the tumor suppressor p53 and several other short-lived proteins including [[p73α]] and ornithine decarboxylase ([[ODC]]). NQO1 binds and stabilizes [[p53]], protecting p53 from ubiquitin-independent 20S proteasomal degradation. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.

The crystal structure of human NQO1 in complex with dicoumarol was determine at 2.75 Å resolution.
NQO1 is a physiological homodimer composed of two interlocked monomers. Each monomer is composed of two domains: a large catalytic domain with α/β fold with flavodoxin topology (residues 1-220) and a small C-terminal domain (residues 221-273). Two catalytic sites are formed and are present at the dimer interface. Two FAD molecules (red) are present; each one is bound to the catalytic domain of each monomer. The dicoumarol molecule (purple) is bound to each of the catalytic sites interacting with FAD and with residues from both monomer.The dicoumarol molecule is bound to each of the catalytic sites interacting with FAD and with residues from both monomers.
[[Image:NQO_Dic copy.jpg|border|center|300px]]
Structural comparison of the apo hNQO1 dimer (PDB accession code 1D4A in cyan) with hNQO1 in complex with dicoumarol(pink) reveals that structural changes associated with dicoumarol binding occur on several residues involving both monomers. The most prominent conformational changes that occur in the presence of dicoumarol involve Tyr 128 and Phe 232 that are present on the surface of the NQO1 catalytic pocket. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.

[[Image:Slid1.jpg|border|center|300px]]

===sna===

NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol

2007-10-21T15:36:05Z

Orly Dym:

== The crystal structure of NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol ==
NAD(P)H quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two electron reduction of quinones to hydroquinones utilizing [[NAD(P)H]] as an electron donor.
NQO1 is a homo-dimer that functions via a “ping pong” mechanism. NAD(P)H binds to NQO1, reduces the [[FAD]] co-factor and is then released, allowing the quinone substrate to bind the enzyme and to be reduced. The NAD(P)H and the quinone binding sites of NQO1 have a significant overlap, thus providing a molecular basis for this “ping pong” mechanism.
Certain coumarins, flavones and the reactive dye cibacron blue are competitive inhibitors of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin))[[Image:Figure3 copy.jpg|border|center|300px]], is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the electron transfer to FAD.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the tumor suppressor p53 and several other short-lived proteins including [[p73α]] and ornithine decarboxylase ([[ODC]]). NQO1 binds and stabilizes [[p53]], protecting p53 from ubiquitin-independent 20S proteasomal degradation. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.

The crystal structure of human NQO1 in complex with dicoumarol was determine at 2.75 Å resolution.
NQO1 is a physiological homodimer composed of two interlocked monomers. Each monomer is composed of two domains: a large catalytic domain with α/β fold with flavodoxin topology (residues 1-220) and a small C-terminal domain (residues 221-273). Two catalytic sites are formed and are present at the dimer interface. Two FAD molecules (red) are present; each one is bound to the catalytic domain of each monomer. The dicoumarol molecule (purple) is bound to each of the catalytic sites interacting with FAD and with residues from both monomer.The dicoumarol molecule is bound to each of the catalytic sites interacting with FAD and with residues from both monomers.
[[Image:NQO_Dic copy.jpg|border|center|300px]]
Structural comparison of the apo hNQO1 dimer (PDB accession code 1D4A) with hNQO1 in complex with dicoumarol reveals that structural changes associated with dicoumarol binding occur on several residues involving both monomers. The most prominent conformational changes that occur in the presence of dicoumarol involve Tyr 128 and Phe 232 that are present on the surface of the NQO1 catalytic pocket. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.

The different residues of NQO1 interacting with dicoumarol with and the conformational changes imposed upon dicoumarol binding.
[[Image:Figure1A copy.jpg|border|center|300px]]

===sna===

File:NQO Dic copy.jpg

2007-10-21T15:04:57Z

Orly Dym:

NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol

2007-10-21T15:03:39Z

Orly Dym:

== The crystal structure of NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol ==
NAD(P)H quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two electron reduction of quinones to hydroquinones utilizing [[NAD(P)H]] as an electron donor.
NQO1 is a homo-dimer that functions via a “ping pong” mechanism. NAD(P)H binds to NQO1, reduces the [[FAD]] co-factor and is then released, allowing the quinone substrate to bind the enzyme and to be reduced. The NAD(P)H and the quinone binding sites of NQO1 have a significant overlap, thus providing a molecular basis for this “ping pong” mechanism.
Certain coumarins, flavones and the reactive dye cibacron blue are competitive inhibitors of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin))[[Image:Figure3 copy.jpg|border|center|300px]], is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the electron transfer to FAD.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the tumor suppressor p53 and several other short-lived proteins including [[p73α]] and ornithine decarboxylase ([[ODC]]). NQO1 binds and stabilizes [[p53]], protecting p53 from ubiquitin-independent 20S proteasomal degradation. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.

The crystal structure of human NQO1 in complex with dicoumarol was determine at 2.75 Å resolution.
NQO1 is a physiological homodimer composed of two interlocked monomers. Each monomer is composed of two domains: a large catalytic domain with α/β fold with flavodoxin topology (residues 1-220) and a small C-terminal domain (residues 221-273). Two catalytic sites are formed and are present at the dimer interface. Two FAD molecules (red) are present; each one is bound to the catalytic domain of each monomer. The dicoumarol molecule (purple) is bound to each of the catalytic sites interacting with FAD and with residues from both monomer.The dicoumarol molecule is bound to each of the catalytic sites interacting with FAD and with residues from both monomers. [[Image:NQO_Dic copy.jpg|border|center|300px]]
The different residues of NQO1 interacting with dicoumarol with and the conformational changes imposed upon dicoumarol binding. The most prominent conformational changes that occur in the presence of dicoumarol involve Tyr 128 and Phe 232 that are present on the surface of the NQO1 catalytic pocket. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.
[[Image:Figure1A copy.jpg|border|center|300px]]

===sna===

NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol

2007-10-21T15:02:26Z

Orly Dym:

== The crystal structure of NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol ==
NAD(P)H quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two electron reduction of quinones to hydroquinones utilizing [[NAD(P)H]] as an electron donor.
NQO1 is a homo-dimer that functions via a “ping pong” mechanism. NAD(P)H binds to NQO1, reduces the [[FAD]] co-factor and is then released, allowing the quinone substrate to bind the enzyme and to be reduced. The NAD(P)H and the quinone binding sites of NQO1 have a significant overlap, thus providing a molecular basis for this “ping pong” mechanism.
Certain coumarins, flavones and the reactive dye cibacron blue are competitive inhibitors of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin))[[Image:Figure3 copy.jpg|border|center|300px]], is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the electron transfer to FAD.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the tumor suppressor p53 and several other short-lived proteins including [[p73α]] and ornithine decarboxylase ([[ODC]]). NQO1 binds and stabilizes [[p53]], protecting p53 from ubiquitin-independent 20S proteasomal degradation. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.

The crystal structure of human NQO1 in complex with dicoumarol was determine at 2.75 Å resolution.
NQO1 is a physiological homodimer composed of two interlocked monomers. Each monomer is composed of two domains: a large catalytic domain with α/β fold with flavodoxin topology (residues 1-220) and a small C-terminal domain (residues 221-273). Two catalytic sites are formed and are present at the dimer interface. Two FAD molecules (red) are present; each one is bound to the catalytic domain of each monomer. The dicoumarol molecule (purple) is bound to each of the catalytic sites interacting with FAD and with residues from both monomer.The dicoumarol molecule is bound to each of the catalytic sites interacting with FAD and with residues from both monomers. [[Image:NQO_Dic copy.jpg]]
The different residues of NQO1 interacting with dicoumarol with and the conformational changes imposed upon dicoumarol binding. The most prominent conformational changes that occur in the presence of dicoumarol involve Tyr 128 and Phe 232 that are present on the surface of the NQO1 catalytic pocket. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.
[[Image:Figure1A copy.jpg]]

===sna===

NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol

2007-10-21T14:58:55Z

Orly Dym:

== The crystal structure of NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol ==
NAD(P)H quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two electron reduction of quinones to hydroquinones utilizing [[NAD(P)H]] as an electron donor.
NQO1 is a homo-dimer that functions via a “ping pong” mechanism. NAD(P)H binds to NQO1, reduces the [[FAD]] co-factor and is then released, allowing the quinone substrate to bind the enzyme and to be reduced. The NAD(P)H and the quinone binding sites of NQO1 have a significant overlap, thus providing a molecular basis for this “ping pong” mechanism.
Certain coumarins, flavones and the reactive dye cibacron blue are competitive inhibitors of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin))[[Image:Figure3 copy.jpg|border|center|300px]], is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the electron transfer to FAD.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the tumor suppressor p53 and several other short-lived proteins including [[p73α]] and ornithine decarboxylase ([[ODC]]). NQO1 binds and stabilizes [[p53]], protecting p53 from ubiquitin-independent 20S proteasomal degradation. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.

The crystal structure of human NQO1 in complex with dicoumarol was determine at 2.75 Å resolution.
NQO1 is a physiological homodimer composed of two interlocked monomers. Each monomer is composed of two domains: a large catalytic domain with α/β fold with flavodoxin topology (residues 1-220) and a small C-terminal domain (residues 221-273). Two catalytic sites are formed and are present at the dimer interface. Two FAD molecules (red) are present; each one is bound to the catalytic domain of each monomer. The dicoumarol molecule (purple) is bound to each of the catalytic sites interacting with FAD and with residues from both monomer.[[Image:[[Image:NQO_Dic.jpgdicoumarol is bound to each of the catalytic sites interacting with FAD and with residues from both monomers]]
The different residues of NQO1 interacting with dicoumarol with and the conformational changes imposed upon dicoumarol binding. The most prominent conformational changes that occur in the presence of dicoumarol involve Tyr 128 and Phe 232 that are present on the surface of the NQO1 catalytic pocket. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.
[[Image:Figure1A copy.jpgc]

===sna===

NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol

2007-10-21T14:54:33Z

Orly Dym:

== The crystal structure of NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol ==
NAD(P)H quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two electron reduction of quinones to hydroquinones utilizing [[NAD(P)H]] as an electron donor.
NQO1 is a homo-dimer that functions via a “ping pong” mechanism. NAD(P)H binds to NQO1, reduces the [[FAD]] co-factor and is then released, allowing the quinone substrate to bind the enzyme and to be reduced. The NAD(P)H and the quinone binding sites of NQO1 have a significant overlap, thus providing a molecular basis for this “ping pong” mechanism.
Certain coumarins, flavones and the reactive dye cibacron blue are competitive inhibitors of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin))[[Image:Figure3 copy.jpg|border|center|300px]], is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the electron transfer to FAD.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the tumor suppressor p53 and several other short-lived proteins including [[p73α]] and ornithine decarboxylase ([[ODC]]). NQO1 binds and stabilizes [[p53]], protecting p53 from ubiquitin-independent 20S proteasomal degradation. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.

The crystal structure of human NQO1 in complex with dicoumarol was determine at 2.75 Å resolution.
NQO1 is a physiological homodimer composed of two interlocked monomers. Each monomer is composed of two domains: a large catalytic domain with α/β fold with flavodoxin topology (residues 1-220) and a small C-terminal domain (residues 221-273). Two catalytic sites are formed and are present at the dimer interface. Two FAD molecules (red) are present; each one is bound to the catalytic domain of each monomer.
The different residues of NQO1 interacting with dicoumarol with and the conformational changes imposed upon dicoumarol binding. The most prominent conformational changes that occur in the presence of dicoumarol involve Tyr 128 and Phe 232 that are present on the surface of the NQO1 catalytic pocket. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.
[[Image:Figure1A copy.jpg|border|center|300px]]

===sna===

NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol

2007-10-21T14:45:37Z

Orly Dym:

== The crystal structure of NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol ==
NAD(P)H quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two electron reduction of quinones to hydroquinones utilizing [[NAD(P)H]] as an electron donor.
NQO1 is a homo-dimer that functions via a “ping pong” mechanism. NAD(P)H binds to NQO1, reduces the [[FAD]] co-factor and is then released, allowing the quinone substrate to bind the enzyme and to be reduced. The NAD(P)H and the quinone binding sites of NQO1 have a significant overlap, thus providing a molecular basis for this “ping pong” mechanism.
Certain coumarins, flavones and the reactive dye cibacron blue are competitive inhibitors of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin))[[Image:Figure3 copy.jpg|border|center|300px]], is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the electron transfer to FAD.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the tumor suppressor p53 and several other short-lived proteins including [[p73α]] and ornithine decarboxylase ([[ODC]]). NQO1 binds and stabilizes [[p53]], protecting p53 from ubiquitin-independent 20S proteasomal degradation. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.

The crystal structure of human NQO1 in complex with dicoumarol was determine at 2.75 Å resolution.
NQO1 is a physiological homodimer composed of two interlocked monomers. Each monomer is composed of two domains: a large catalytic domain with α/β fold with flavodoxin topology (residues 1-220) and a small C-terminal domain (residues 221-273). Two catalytic sites are formed and are present at the dimer interface. Two FAD molecules are present; each one is bound to the catalytic domain of each monomer. The FAD moiety in the catalytic domain of one of the monomers forms one wall of the catalytic pocket, while residues from both monomers generate the other walls (5, 28).

The different residues of NQO1 interacting with dicoumarol with and the conformational changes imposed upon dicoumarol binding. The most prominent conformational changes that occur in the presence of dicoumarol involve Tyr 128 and Phe 232 that are present on the surface of the NQO1 catalytic pocket. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.
[[Image:Figure1A copy.jpg|border|center|300px]]

===sna===

NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol

2007-10-21T14:36:03Z

Orly Dym:

== The crystal structure of NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol ==
NAD(P)H quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two electron reduction of quinones to hydroquinones utilizing [[NAD(P)H]] as an electron donor.
NQO1 is a homo-dimer that functions via a “ping pong” mechanism. NAD(P)H binds to NQO1, reduces the [[FAD]] co-factor and is then released, allowing the quinone substrate to bind the enzyme and to be reduced. The NAD(P)H and the quinone binding sites of NQO1 have a significant overlap, thus providing a molecular basis for this “ping pong” mechanism.
Certain coumarins, flavones and the reactive dye cibacron blue are competitive inhibitors of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin))[[Image:Figure3 copy.jpg|border|center|300px]], is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the electron transfer to FAD.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the tumor suppressor p53 and several other short-lived proteins including [[p73α]] and ornithine decarboxylase ([[ODC]]). NQO1 binds and stabilizes [[p53]], protecting p53 from ubiquitin-independent 20S proteasomal degradation. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.

NQO1 binds and stabilizes several short-lived proteins including the tumor suppressors [[p53]] and [[p73]] and the enzyme ornithine decarboxylase ([[ODC]]). [[Dicoumarol]] is a widely used potent competitive inhibitor of NQO1 enzymatic activity, which competes with NAD(P)H for binding to NQO1. Dicoumarol also disrupts the binding of NQO1 to p53, p73 and ODC and induces their ubiquitin-independent proteasomal degradation. The crystal structure of human NQO1 in complex with dicoumarol was determine at 2.75 Å resolution. The different residues of NQO1 interacting with dicoumarol with and the conformational changes imposed upon dicoumarol binding. The most prominent conformational changes that occur in the presence of dicoumarol involve Tyr 128 and Phe 232 that are present on the surface of the NQO1 catalytic pocket. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.
[[Image:Figure1A copy.jpg|border|center|300px]]

===sna===

NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol

2007-10-21T14:35:07Z

Orly Dym:

== The crystal structure of NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol ==
NAD(P)H quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two electron reduction of quinones to hydroquinones utilizing [[NAD(P)H]] as an electron donor.
NQO1 is a homo-dimer that functions via a “ping pong” mechanism. NAD(P)H binds to NQO1, reduces the [[FAD]] co-factor and is then released, allowing the quinone substrate to bind the enzyme and to be reduced. The NAD(P)H and the quinone binding sites of NQO1 have a significant overlap, thus providing a molecular basis for this “ping pong” mechanism.
Certain coumarins, flavones and the reactive dye cibacron blue are competitive inhibitors of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin))[[Image:Figure 3 copy.jpg|border|center|300px]], is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the electron transfer to FAD.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the tumor suppressor p53 and several other short-lived proteins including [[p73α]] and ornithine decarboxylase ([[ODC]]). NQO1 binds and stabilizes [[p53]], protecting p53 from ubiquitin-independent 20S proteasomal degradation. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.

NQO1 binds and stabilizes several short-lived proteins including the tumor suppressors [[p53]] and [[p73]] and the enzyme ornithine decarboxylase ([[ODC]]). [[Dicoumarol]] is a widely used potent competitive inhibitor of NQO1 enzymatic activity, which competes with NAD(P)H for binding to NQO1. Dicoumarol also disrupts the binding of NQO1 to p53, p73 and ODC and induces their ubiquitin-independent proteasomal degradation. The crystal structure of human NQO1 in complex with dicoumarol was determine at 2.75 Å resolution. The different residues of NQO1 interacting with dicoumarol with and the conformational changes imposed upon dicoumarol binding. The most prominent conformational changes that occur in the presence of dicoumarol involve Tyr 128 and Phe 232 that are present on the surface of the NQO1 catalytic pocket. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.
[[Image:Figure1A copy.jpg|border|center|300px]]

===sna===

File:Figure3 copy.jpg

2007-10-21T14:34:11Z

Orly Dym:

NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol

2007-10-21T14:31:29Z

Orly Dym:

== The crystal structure of NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol ==
NAD(P)H quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two electron reduction of quinones to hydroquinones utilizing [[NAD(P)H]] as an electron donor.
NQO1 is a homo-dimer that functions via a “ping pong” mechanism. NAD(P)H binds to NQO1, reduces the [[FAD]] co-factor and is then released, allowing the quinone substrate to bind the enzyme and to be reduced. The NAD(P)H and the quinone binding sites of NQO1 have a significant overlap, thus providing a molecular basis for this “ping pong” mechanism.
Certain coumarins, flavones and the reactive dye cibacron blue are competitive inhibitors of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin))[[Image:Figure3|border|center|300px]], is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the electron transfer to FAD.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the tumor suppressor p53 and several other short-lived proteins including [[p73α]] and ornithine decarboxylase ([[ODC]]). NQO1 binds and stabilizes [[p53]], protecting p53 from ubiquitin-independent 20S proteasomal degradation. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.

NQO1 binds and stabilizes several short-lived proteins including the tumor suppressors [[p53]] and [[p73]] and the enzyme ornithine decarboxylase ([[ODC]]). [[Dicoumarol]] is a widely used potent competitive inhibitor of NQO1 enzymatic activity, which competes with NAD(P)H for binding to NQO1. Dicoumarol also disrupts the binding of NQO1 to p53, p73 and ODC and induces their ubiquitin-independent proteasomal degradation. The crystal structure of human NQO1 in complex with dicoumarol was determine at 2.75 Å resolution. The different residues of NQO1 interacting with dicoumarol with and the conformational changes imposed upon dicoumarol binding. The most prominent conformational changes that occur in the presence of dicoumarol involve Tyr 128 and Phe 232 that are present on the surface of the NQO1 catalytic pocket. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.
[[Image:Figure1A copy.jpg|border|center|300px]]

===sna===

NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol

2007-10-21T14:13:45Z

Orly Dym:

== The crystal structure of NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol ==
NAD(P)H quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two electron reduction of quinones to hydroquinones utilizing [[NAD(P)H]] as an electron donor.
NQO1 is a homo-dimer that functions via a “ping pong” mechanism. NAD(P)H binds to NQO1, reduces the [[FAD]] co-factor and is then released, allowing the quinone substrate to bind the enzyme and to be reduced. The NAD(P)H and the quinone binding sites of NQO1 have a significant overlap, thus providing a molecular basis for this “ping pong” mechanism.
Certain coumarins, flavones and the reactive dye cibacron blue are competitive inhibitors of NQO1 activity, which compete with NAD(P)H for binding to NQO1. [[Dicoumarol]] (3-3’–methylene-bis (4-hydroxycoumarin)), is the most potent competitive inhibitor of NQO1. Dicoumarol competes with NAD(P)H for binding to NQO1 and prevents the electron transfer to FAD.
In addition to its role in the detoxification of quinones, NQO1 is also a 20S proteasome-associated protein that plays an important role in the stability of the tumor suppressor p53 and several other short-lived proteins including [[p73α]] and ornithine decarboxylase ([[ODC]]). NQO1 binds and stabilizes [[p53]], protecting p53 from ubiquitin-independent 20S proteasomal degradation. Dicoumarol and several other inhibitors of NQO1 activity, which compete with NADH for binding to NQO1, disrupt the binding of NQO1 to p53 and induce ubiquitin-independent p53 degradation.

NQO1 binds and stabilizes several short-lived proteins including the tumor suppressors [[p53]] and [[p73]] and the enzyme ornithine decarboxylase ([[ODC]]). [[Dicoumarol]] is a widely used potent competitive inhibitor of NQO1 enzymatic activity, which competes with NAD(P)H for binding to NQO1. Dicoumarol also disrupts the binding of NQO1 to p53, p73 and ODC and induces their ubiquitin-independent proteasomal degradation. The crystal structure of human NQO1 in complex with dicoumarol was determine at 2.75 Å resolution. The different residues of NQO1 interacting with dicoumarol with and the conformational changes imposed upon dicoumarol binding. The most prominent conformational changes that occur in the presence of dicoumarol involve Tyr 128 and Phe 232 that are present on the surface of the NQO1 catalytic pocket. Based on the comparison of NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutations that affect NQO1 interactions we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.
[[Image:Figure1A copy.jpg|border|center|300px]]

===sna===