6nh3: Difference between revisions
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<StructureSection load='6nh3' size='340' side='right'caption='[[6nh3]], [[Resolution|resolution]] 2.01Å' scene=''> | <StructureSection load='6nh3' size='340' side='right'caption='[[6nh3]], [[Resolution|resolution]] 2.01Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6nh3]] is a 4 chain structure with sequence from [ | <table><tr><td colspan='2'>[[6nh3]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NH3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NH3 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=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=KL4:6-[2-(3-fluoro-5-{2-[(2S)-pyrrolidin-2-yl]ethyl}phenyl)ethyl]-4-methylpyridin-2-amine'>KL4</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]] 2.01Å</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=KL4:6-[2-(3-fluoro-5-{2-[(2S)-pyrrolidin-2-yl]ethyl}phenyl)ethyl]-4-methylpyridin-2-amine'>KL4</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=6nh3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nh3 OCA], [https://pdbe.org/6nh3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nh3 RCSB], [https://www.ebi.ac.uk/pdbsum/6nh3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nh3 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Chreifi | [[Category: Chreifi G]] | ||
[[Category: Li | [[Category: Li H]] | ||
[[Category: Poulos | [[Category: Poulos TL]] | ||
Latest revision as of 09:53, 11 October 2023
Structure of human endothelial nitric oxide synthase heme domain in complex with (S)-6-(3-fluoro-5-(2-(pyrrolidin-2-yl)ethyl)phenethyl)-4-methylpyridin-2-amineStructure of human endothelial nitric oxide synthase heme domain in complex with (S)-6-(3-fluoro-5-(2-(pyrrolidin-2-yl)ethyl)phenethyl)-4-methylpyridin-2-amine
Structural highlights
FunctionNOS3_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 PubMedEffective delivery of therapeutic drugs into the human brain is one of the most challenging tasks in central nervous system drug development because of the blood-brain barrier (BBB). To overcome the BBB, both passive permeability and efflux transporter liability of a compound must be addressed. Herein, we report our optimization related to BBB penetration of neuronal nitric oxide synthase (nNOS) inhibitors toward the development of new drugs for neurodegenerative diseases. Various approaches, including enhancing lipophilicity and rigidity of new inhibitors and modulating the p Ka of amino groups, have been employed. In addition to determining inhibitor potency and selectivity, crystal structures of most newly designed compounds complexed to various nitric oxide synthase isoforms have been determined. We have discovered a new analogue (21), which exhibits not only excellent potency ( Ki < 30 nM) in nNOS inhibition but also a significantly low P-glycoprotein and breast-cancer-resistant protein substrate liability as indicated by an efflux ratio of 0.8 in the Caco-2 bidirectional assay. Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold.,Do HT, Li H, Chreifi G, Poulos TL, Silverman RB J Med Chem. 2019 Feb 25. doi: 10.1021/acs.jmedchem.8b02032. PMID:30802056[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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