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[[Image:1dmk.gif|left|200px]]


{{Structure
==BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 4-AMINO-6-PHENYL-TETRAHYDROPTERIDINE==
|PDB= 1dmk |SIZE=350|CAPTION= <scene name='initialview01'>1dmk</scene>, resolution 1.90&Aring;
<StructureSection load='1dmk' size='340' side='right'caption='[[1dmk]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
|SITE=  
== Structural highlights ==
|LIGAND= <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CAC:CACODYLATE+ION'>CAC</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=AP6:2,4-DIAMINO-6-PHENYL-5,6,7,8,-TETRAHYDROPTERIDINE'>AP6</scene> and <scene name='pdbligand=ITU:ETHYLISOTHIOUREA'>ITU</scene>
<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>
|ACTIVITY= [http://en.wikipedia.org/wiki/Nitric-oxide_synthase Nitric-oxide synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.39 1.14.13.39]  
</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>
|GENE=  
<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='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.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/dm/1dmk_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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.


'''BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 4-AMINO-6-PHENYL-TETRAHYDROPTERIDINE'''
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>


==Overview==
==See Also==
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.
*[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]]
 
== References ==
==About this Structure==
<references/>
1DMK is a [[Single protein]] structure of sequence from [http://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].
__TOC__
 
</StructureSection>
==Reference==
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:[http://www.ncbi.nlm.nih.gov/pubmed/11590164 11590164]
[[Category: Bos taurus]]
[[Category: Bos taurus]]
[[Category: Nitric-oxide synthase]]
[[Category: Large Structures]]
[[Category: Single protein]]
[[Category: Al-Masoudi N]]
[[Category: Al-Masoudi, N.]]
[[Category: Berg M]]
[[Category: Berg, M.]]
[[Category: Frohlich LG]]
[[Category: Frohlich, L G.]]
[[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 BS]]
[[Category: Masters, B S.]]
[[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 CS]]
[[Category: Raman, C S.]]
[[Category: Schmidt HH]]
[[Category: Schmidt, H H.]]
[[Category: Schnabel J]]
[[Category: Schnabel, J.]]
[[Category: Strobel H]]
[[Category: Strobel, H.]]
[[Category: Taghavi-Moghadam S]]
[[Category: Taghavi-Moghadam, S.]]
[[Category: ACT]]
[[Category: AP6]]
[[Category: CAC]]
[[Category: HEM]]
[[Category: ITU]]
[[Category: ZN]]
[[Category: alpha-beta fold]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 10:40:50 2008''
Retrieved from "https://proteopedia.org/1dmk"