View source for 4d3a


==Structure of bovine endothelial nitric oxide synthase heme domain in complex with 3-(3-fluorophenyl)-N-2-(2-(5-methyl-1H-imidazol-1-yl) pyrimidin-4-yl)ethylpropan-1-amine==
<StructureSection load='4d3a' size='340' side='right' caption='[[4d3a]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4d3a]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4D3A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D3A FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7F5:3-(3-FLUOROPHENYL)-N-{2-[2-(5-METHYL-1H-IMIDAZOL-1-YL)PYRIMIDIN-4-YL]ETHYL}PROPAN-1-AMINE'>7F5</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=H4B:5,6,7,8-TETRAHYDROBIOPTERIN'>H4B</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CAS:S-(DIMETHYLARSENIC)CYSTEINE'>CAS</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4d2y|4d2y]], [[4d2z|4d2z]], [[4d30|4d30]], [[4d31|4d31]], [[4d32|4d32]], [[4d33|4d33]], [[4d34|4d34]], [[4d35|4d35]], [[4d36|4d36]], [[4d37|4d37]], [[4d38|4d38]], [[4d39|4d39]], [[4d3b|4d3b]], [[4v3u|4v3u]], [[4v3v|4v3v]], [[4v3w|4v3w]], [[4v3x|4v3x]], [[4v3y|4v3y]], [[4v3z|4v3z]]</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Nitric-oxide_synthase_(NADPH_dependent) Nitric-oxide synthase (NADPH dependent)], with EC number [http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4d3a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d3a OCA], [http://pdbe.org/4d3a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4d3a RCSB], [http://www.ebi.ac.uk/pdbsum/4d3a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4d3a ProSAT]</span></td></tr>
</table>
== Function ==
[[http://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. 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Selective inhibition of neuronal nitric oxide synthase (nNOS) is an important therapeutic approach to target neurodegenerative disorders. However, the majority of the nNOS inhibitors developed are arginine mimetics and, therefore, suffer from poor bioavailability. We designed a novel strategy to combine a more pharmacokinetically favorable 2-imidazolylpyrimidine head with promising structural components from previous inhibitors. In conjunction with extensive structure-activity studies, several highly potent and selective inhibitors of nNOS were discovered. X-ray crystallographic analysis reveals that these type II inhibitors utilize the same hydrophobic pocket to gain strong inhibitory potency (13), as well as high isoform selectivity. Interestingly, select compounds from this series (9) showed good permeability and low efflux in a Caco-2 assay, suggesting potential oral bioavailability, and exhibited minimal off-target binding to 50 central nervous system receptors. Furthermore, even with heme-coordinating groups in the molecule, modifying other pharmacophoric fragments minimized undesirable inhibition of cytochrome P450s from human liver microsomes.

Novel 2,4-Disubstituted Pyrimidines as Potent, Selective, and Cell-permeable Inhibitors of Neuronal Nitric Oxide Synthase.,Mukherjee P, Li H, Sevrioukova IF, Chreifi G, Martasek P, Roman LJ, Poulos TL, Silverman RB J Med Chem. 2014 Dec 9. PMID:25489882<ref>PMID:25489882</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4d3a" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Chreifi, G]]
[[Category: Li, H]]
[[Category: Poulos, T L]]
[[Category: Inhibitor complex]]
[[Category: Nitric oxide synthase]]
[[Category: Oxidoreductase]]