6av7: Difference between revisions
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==Structure of human endothelial nitric oxide synthase heme domain in complex with HW69== | |||
<StructureSection load='6av7' size='340' side='right' caption='[[6av7]], [[Resolution|resolution]] 1.92Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6av7]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6AV7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6AV7 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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=W69:6-(2-{3-[3-(dimethylamino)propyl]-5-fluorophenyl}ethyl)-4-methylpyridin-2-amine'>W69</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">[[6aur|6aur]], [[6aut|6aut]], [[6auq|6auq]], [[6aus|6aus]], [[6auz|6auz]], [[6av1|6av1]], [[6auy|6auy]], [[6av0|6av0]], [[6av2|6av2]], [[6av6|6av6]], [[6auu|6auu]], [[6auv|6auv]], [[6auw|6auw]], [[6aux|6aux]], [[6av3|6av3]], [[6av4|6av4]], [[6av5|6av5]]</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=6av7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6av7 OCA], [http://pdbe.org/6av7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6av7 RCSB], [http://www.ebi.ac.uk/pdbsum/6av7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6av7 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/NOS3_HUMAN 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.<ref>PMID:17264164</ref> Isoform eNOS13C: Lacks eNOS activity, dominant-negative form that may down-regulate eNOS activity by forming heterodimers with isoform 1.<ref>PMID:17264164</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Inhibition of neuronal nitric oxide synthase (nNOS) is a promising therapeutic approach to treat neurodegenerative diseases. Recently, we have achieved considerable progress in improving the potency and isoform selectivity of human nNOS inhibitors bearing a 2-aminopyridine scaffold. However, these inhibitors still suffered from too low cell membrane permeability to enter into CNS drug development. We report herein our studies to improve permeability of nNOS inhibitors as measured by both PAMPA-BBB and Caco-2 assays. The most permeable compound (12) in this study still preserves excellent potency with human nNOS (Ki = 30 nM) and very high selectivity over other NOS isoforms, especially human eNOS (hnNOS/heNOS = 2799, the highest hnNOS/heNOS ratio we have obtained to date). X-ray crystallographic analysis reveals that 12 adopts a similar binding mode in both rat and human nNOS, in which the 2-aminopyridine and the fluorobenzene linker form crucial hydrogen bonds with glutamate and tyrosine residues, respectively. | |||
Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker.,Do HT, Wang HY, Li H, Chreifi G, Poulos TL, Silverman RB J Med Chem. 2017 Nov 22;60(22):9360-9375. doi: 10.1021/acs.jmedchem.7b01356. Epub, 2017 Nov 1. PMID:29091437<ref>PMID:29091437</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6av7" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Li, H]] | [[Category: Li, H]] | ||
[[Category: Poulos, T | [[Category: Poulos, T L]] | ||
[[Category: Nitric oxide synthase inhibitor complex heme enzyme]] | |||
[[Category: Oxidoreductase]] | |||
Revision as of 08:42, 11 July 2018
Structure of human endothelial nitric oxide synthase heme domain in complex with HW69Structure of human endothelial nitric oxide synthase heme domain in complex with HW69
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 PubMedInhibition of neuronal nitric oxide synthase (nNOS) is a promising therapeutic approach to treat neurodegenerative diseases. Recently, we have achieved considerable progress in improving the potency and isoform selectivity of human nNOS inhibitors bearing a 2-aminopyridine scaffold. However, these inhibitors still suffered from too low cell membrane permeability to enter into CNS drug development. We report herein our studies to improve permeability of nNOS inhibitors as measured by both PAMPA-BBB and Caco-2 assays. The most permeable compound (12) in this study still preserves excellent potency with human nNOS (Ki = 30 nM) and very high selectivity over other NOS isoforms, especially human eNOS (hnNOS/heNOS = 2799, the highest hnNOS/heNOS ratio we have obtained to date). X-ray crystallographic analysis reveals that 12 adopts a similar binding mode in both rat and human nNOS, in which the 2-aminopyridine and the fluorobenzene linker form crucial hydrogen bonds with glutamate and tyrosine residues, respectively. Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker.,Do HT, Wang HY, Li H, Chreifi G, Poulos TL, Silverman RB J Med Chem. 2017 Nov 22;60(22):9360-9375. doi: 10.1021/acs.jmedchem.7b01356. Epub, 2017 Nov 1. PMID:29091437[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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