1dmk: Difference between revisions

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== Structural highlights ==

<table><tr><td colspan='2'>[[1dmk]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Bovin Bovin~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DMK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1DMK FirstGlance]. <br>

<table><tr><td colspan='2'>[[1dmk]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DMK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1DMK FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=AP6:2,4-DIAMINO-6-PHENYL-5,6,7,8,-TETRAHYDROPTERIDINE'>AP6</scene>, <scene name='pdbligand=CAC:CACODYLATE+ION'>CAC</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=ITU:ETHYLISOTHIOUREA'>ITU</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 1.9Å</td></tr>

~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1nse|1nse]]</div></td></tr>~~

<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=AP6:2,4-DIAMINO-6-PHENYL-5,6,7,8,-TETRAHYDROPTERIDINE'>AP6</scene>, <scene name='pdbligand=CAC:CACODYLATE+ION'>CAC</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=ITU:ETHYLISOTHIOUREA'>ITU</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>

<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Nitric-oxide_synthase_(NADPH_dependent) Nitric-oxide synthase (NADPH dependent)], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.39 1.14.13.39] </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=1dmk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1dmk OCA], [https://pdbe.org/1dmk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1dmk RCSB], [https://www.ebi.ac.uk/pdbsum/1dmk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1dmk ProSAT]</span></td></tr>

</table>

== Function ==

[[https://www.uniprot.org/uniprot/NOS3_BOVIN NOS3_BOVIN]] Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets.

[https://www.uniprot.org/uniprot/NOS3_BOVIN NOS3_BOVIN] Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets.

== Evolutionary Conservation ==

[[Image:Consurf_key_small.gif|200px|right]]

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Line 20:

</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1dmk ConSurf].

~~<div style="background-color:#fffaf0;">~~

~~== Publication Abstract from PubMed ==~~

Pathological nitric oxide (NO) generation in sepsis, inflammation, and stroke may be therapeutically controlled by inhibiting NO synthases (NOS). Here we targeted the (6R)-5,6,7,8-tetrahydro-l-biopterin (H(4)Bip)-binding site of NOS, which, upon cofactor binding, maximally increases enzyme activity and NO production from substrate l-arginine. The first generation of H(4)Bip-based NOS inhibitors employed a 4-amino pharmacophore of H(4)Bip analogous to antifolates such as methotrexate. We developed a novel series of 4-oxo-pteridine derivatives that were screened for inhibition against neuronal NOS (NOS-I) and a structure-activity relationship was determined. To understand the structural basis for pterin antagonism, selected derivatives were docked into the NOS pterin binding cavity. Using a reduced 4-oxo-pteridine scaffold, derivatives with certain modifications such as electron-rich aromatic phenyl or benzoyl groups at the 5- and 6-positions, were discovered to markedly inhibit NOS-I, possibly due to hydrophobic and electrostatic interactions with Phe(462) and Ser(104), respectively, within the pterin binding pocket. One of the most effective 4-oxo compounds and, for comparisons an active 4-amino derivative, were then co-crystallized with the endothelial NOS (NOS-III) oxygenase domain and this structure solved to confirm the hypothetical binding modes. Collectively, these findings suggest (i) that, unlike the antifolate principle, the 4-amino substituent is not essential for developing pterin-based NOS inhibitors and (ii), provide a steric and electrostatic basis for their rational design.

Structural basis for pterin antagonism in nitric-oxide synthase. Development of novel 4-oxo-pteridine antagonists of (6R)-5,6,7,8-tetrahydrobiopterin.,Kotsonis P, Frohlich LG, Raman CS, Li H, Berg M, Gerwig R, Groehn V, Kang Y, Al-Masoudi N, Taghavi-Moghadam S, Mohr D, Munch U, Schnabel J, Martasek P, Masters BS, Strobel H, Poulos T, Matter H, Pfleiderer W, Schmidt HH J Biol Chem. 2001 Dec 28;276(52):49133-41. Epub 2001 Oct 5. PMID:11590164<ref>PMID:11590164</ref>

~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~

~~</div>~~

~~<div class="pdbe-citations 1dmk" style="background-color:#fffaf0;"></div>~~

==See Also==

*[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]]

~~== References ==~~

~~<references/>~~

__TOC__

</StructureSection>

[[Category: ~~Bovin~~]]

[[Category: Bos taurus]]

[[Category: Large Structures]]

[[Category: Al-Masoudi, N]]

[[Category: Al-Masoudi N]]

[[Category: Berg, M]]

[[Category: Berg M]]

[[Category: Frohlich~~, L G~~]]

[[Category: Frohlich LG]]

[[Category: Gerwig, R]]

[[Category: Gerwig R]]

[[Category: Groehn, V]]

[[Category: Groehn V]]

[[Category: Kang, Y]]

[[Category: Kang Y]]

[[Category: Kotsonis, P]]

[[Category: Kotsonis P]]

[[Category: Li, H]]

[[Category: Li H]]

[[Category: Martasek, P]]

[[Category: Martasek P]]

[[Category: Masters~~, B S~~]]

[[Category: Masters BS]]

[[Category: Matter, H]]

[[Category: Matter H]]

[[Category: Mohr, D]]

[[Category: Mohr D]]

[[Category: Munch, U]]

[[Category: Munch U]]

[[Category: Pfleiderer, W]]

[[Category: Pfleiderer W]]

[[Category: Poulos, T]]

[[Category: Poulos T]]

[[Category: Raman~~, C S~~]]

[[Category: Raman CS]]

[[Category: Schmidt~~, H H~~]]

[[Category: Schmidt HH]]

[[Category: Schnabel, J]]

[[Category: Schnabel J]]

[[Category: Strobel, H]]

[[Category: Strobel H]]

[[Category: Taghavi-Moghadam, S]]

[[Category: Taghavi-Moghadam S]]

~~[[Category: Alpha-beta fold]]~~

~~[[Category: Oxidoreductase~~]]

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@@ Line 3: / Line 3: @@
 <StructureSection load='1dmk' size='340' side='right'caption='[[1dmk]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1dmk]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bovin Bovin]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DMK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1DMK FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1dmk]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DMK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1DMK FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=AP6:2,4-DIAMINO-6-PHENYL-5,6,7,8,-TETRAHYDROPTERIDINE'>AP6</scene>, <scene name='pdbligand=CAC:CACODYLATE+ION'>CAC</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=ITU:ETHYLISOTHIOUREA'>ITU</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 1.9&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1nse|1nse]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=AP6:2,4-DIAMINO-6-PHENYL-5,6,7,8,-TETRAHYDROPTERIDINE'>AP6</scene>, <scene name='pdbligand=CAC:CACODYLATE+ION'>CAC</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=ITU:ETHYLISOTHIOUREA'>ITU</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Nitric-oxide_synthase_(NADPH_dependent) Nitric-oxide synthase (NADPH dependent)], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.39 1.14.13.39] </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=1dmk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1dmk OCA], [https://pdbe.org/1dmk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1dmk RCSB], [https://www.ebi.ac.uk/pdbsum/1dmk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1dmk ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/NOS3_BOVIN NOS3_BOVIN]] Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets.
+[https://www.uniprot.org/uniprot/NOS3_BOVIN NOS3_BOVIN] Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets.
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 21: / Line 20: @@
 </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1dmk ConSurf].
 <div style="clear:both"></div>
-<div style="background-color:#fffaf0;">
-== Publication Abstract from PubMed ==
-Pathological nitric oxide (NO) generation in sepsis, inflammation, and stroke may be therapeutically controlled by inhibiting NO synthases (NOS). Here we targeted the (6R)-5,6,7,8-tetrahydro-l-biopterin (H(4)Bip)-binding site of NOS, which, upon cofactor binding, maximally increases enzyme activity and NO production from substrate l-arginine. The first generation of H(4)Bip-based NOS inhibitors employed a 4-amino pharmacophore of H(4)Bip analogous to antifolates such as methotrexate. We developed a novel series of 4-oxo-pteridine derivatives that were screened for inhibition against neuronal NOS (NOS-I) and a structure-activity relationship was determined. To understand the structural basis for pterin antagonism, selected derivatives were docked into the NOS pterin binding cavity. Using a reduced 4-oxo-pteridine scaffold, derivatives with certain modifications such as electron-rich aromatic phenyl or benzoyl groups at the 5- and 6-positions, were discovered to markedly inhibit NOS-I, possibly due to hydrophobic and electrostatic interactions with Phe(462) and Ser(104), respectively, within the pterin binding pocket. One of the most effective 4-oxo compounds and, for comparisons an active 4-amino derivative, were then co-crystallized with the endothelial NOS (NOS-III) oxygenase domain and this structure solved to confirm the hypothetical binding modes. Collectively, these findings suggest (i) that, unlike the antifolate principle, the 4-amino substituent is not essential for developing pterin-based NOS inhibitors and (ii), provide a steric and electrostatic basis for their rational design.
-Structural basis for pterin antagonism in nitric-oxide synthase. Development of novel 4-oxo-pteridine antagonists of (6R)-5,6,7,8-tetrahydrobiopterin.,Kotsonis P, Frohlich LG, Raman CS, Li H, Berg M, Gerwig R, Groehn V, Kang Y, Al-Masoudi N, Taghavi-Moghadam S, Mohr D, Munch U, Schnabel J, Martasek P, Masters BS, Strobel H, Poulos T, Matter H, Pfleiderer W, Schmidt HH J Biol Chem. 2001 Dec 28;276(52):49133-41. Epub 2001 Oct 5. PMID:11590164<ref>PMID:11590164</ref>
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 1dmk" style="background-color:#fffaf0;"></div>
 ==See Also==
 *[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]]
-== References ==
-<references/>
 __TOC__
 </StructureSection>
-[[Category: Bovin]]
+[[Category: Bos taurus]]
 [[Category: Large Structures]]
-[[Category: Al-Masoudi, N]]
+[[Category: Al-Masoudi N]]
-[[Category: Berg, M]]
+[[Category: Berg M]]
-[[Category: Frohlich, L G]]
+[[Category: Frohlich LG]]
-[[Category: Gerwig, R]]
+[[Category: Gerwig R]]
-[[Category: Groehn, V]]
+[[Category: Groehn V]]
-[[Category: Kang, Y]]
+[[Category: Kang Y]]
-[[Category: Kotsonis, P]]
+[[Category: Kotsonis P]]
-[[Category: Li, H]]
+[[Category: Li H]]
-[[Category: Martasek, P]]
+[[Category: Martasek P]]
-[[Category: Masters, B S]]
+[[Category: Masters BS]]
-[[Category: Matter, H]]
+[[Category: Matter H]]
-[[Category: Mohr, D]]
+[[Category: Mohr D]]
-[[Category: Munch, U]]
+[[Category: Munch U]]
-[[Category: Pfleiderer, W]]
+[[Category: Pfleiderer W]]
-[[Category: Poulos, T]]
+[[Category: Poulos T]]
-[[Category: Raman, C S]]
+[[Category: Raman CS]]
-[[Category: Schmidt, H H]]
+[[Category: Schmidt HH]]
-[[Category: Schnabel, J]]
+[[Category: Schnabel J]]
-[[Category: Strobel, H]]
+[[Category: Strobel H]]
-[[Category: Taghavi-Moghadam, S]]
+[[Category: Taghavi-Moghadam S]]
-[[Category: Alpha-beta fold]]
-[[Category: Oxidoreductase]]