5vvc: Difference between revisions
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<StructureSection load='5vvc' size='340' side='right' caption='[[5vvc]], [[Resolution|resolution]] 2.40Å' scene=''> | <StructureSection load='5vvc' size='340' side='right' caption='[[5vvc]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5vvc]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VVC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VVC FirstGlance]. <br> | <table><tr><td colspan='2'>[[5vvc]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VVC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VVC FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9OJ:4-(2-{[(2-amino-4-methylquinolin-7-yl)methyl]amino}ethyl)-2-methylbenzonitrile'>9OJ</scene>, <scene name='pdbligand=BTB:2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>BTB</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GD:GADOLINIUM+ATOM'>GD</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> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9OJ:4-(2-{[(2-amino-4-methylquinolin-7-yl)methyl]amino}ethyl)-2-methylbenzonitrile'>9OJ</scene>, <scene name='pdbligand=BTB:2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>BTB</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GD:GADOLINIUM+ATOM'>GD</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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5vvd|5vvd]], [[5vv2|5vv2]], [[5vv4|5vv4]], [[5vuv|5vuv]], [[5vuz|5vuz]], [[5vv1|5vv1]], [[5vuw|5vuw]], [[5vux|5vux]], [[5vuy|5vuy]], [[5vv3|5vv3]], [[5vv5|5vv5]], [[5vvb|5vvb]], [[5vv0|5vv0]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5vvd|5vvd]], [[5vv2|5vv2]], [[5vv4|5vv4]], [[5vuv|5vuv]], [[5vuz|5vuz]], [[5vv1|5vv1]], [[5vuw|5vuw]], [[5vux|5vux]], [[5vuy|5vuy]], [[5vv3|5vv3]], [[5vv5|5vv5]], [[5vvb|5vvb]], [[5vv0|5vv0]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NOS3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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='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=5vvc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vvc OCA], [http://pdbe.org/5vvc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5vvc RCSB], [http://www.ebi.ac.uk/pdbsum/5vvc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5vvc ProSAT]</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=5vvc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vvc OCA], [http://pdbe.org/5vvc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5vvc RCSB], [http://www.ebi.ac.uk/pdbsum/5vvc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5vvc ProSAT]</span></td></tr> | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Chreifi, G]] | [[Category: Chreifi, G]] | ||
[[Category: Li, H]] | [[Category: Li, H]] | ||
Revision as of 23:08, 15 November 2017
Structure of human endothelial nitric oxide synthase heme domain in complex with 4-(2-(((2-Amino-4-methylquinolin-7-yl)methyl)amino)ethyl)-2-methylbenzonitrileStructure of human endothelial nitric oxide synthase heme domain in complex with 4-(2-(((2-Amino-4-methylquinolin-7-yl)methyl)amino)ethyl)-2-methylbenzonitrile
Structural highlights
Function[NOS3_HUMAN] 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.[1] Isoform eNOS13C: Lacks eNOS activity, dominant-negative form that may down-regulate eNOS activity by forming heterodimers with isoform 1.[2] Publication Abstract from PubMedNeuronal nitric oxide synthase (nNOS) is a target for development of antineurodegenerative agents. Most nNOS inhibitors mimic l-arginine and have poor bioavailability. 2-Aminoquinolines showed promise as bioavailable nNOS inhibitors but suffered from low human nNOS inhibition, low selectivity versus human eNOS, and significant binding to other CNS targets. We aimed to improve human nNOS potency and selectivity and reduce off-target binding by (a) truncating the original scaffold or (b) introducing a hydrophilic group to interrupt the lipophilic, promiscuous pharmacophore and promote interaction with human nNOS-specific His342. We synthesized both truncated and polar 2-aminoquinoline derivatives and assayed them against recombinant NOS enzymes. Although aniline and pyridine derivatives interact with His342, benzonitriles conferred the best rat and human nNOS inhibition. Both introduction of a hydrophobic substituent next to the cyano group and aminoquinoline methylation considerably improved isoform selectivity. Most importantly, these modifications preserved Caco-2 permeability and reduced off-target CNS binding. Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors.,Pensa AV, Cinelli MA, Li H, Chreifi G, Mukherjee P, Roman LJ, Martasek P, Poulos TL, Silverman RB J Med Chem. 2017 Aug 4. doi: 10.1021/acs.jmedchem.7b00835. PMID:28776992[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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