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==Structure of human nNOS R354A G357D mutant heme domain in complex with 4-methyl-6-(2-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)ethyl) pyridin-2-amine== | ==Structure of human nNOS R354A G357D mutant heme domain in complex with 4-methyl-6-(2-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)ethyl) pyridin-2-amine== | ||
<StructureSection load='5fvu' size='340' side='right' caption='[[5fvu]], [[Resolution|resolution]] 2.22Å' scene=''> | <StructureSection load='5fvu' size='340' side='right'caption='[[5fvu]], [[Resolution|resolution]] 2.22Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5fvu]] is a 2 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=5FVU OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[5fvu]] is a 2 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=5FVU OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5FVU FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=W64:4-METHYL-6-(2-(5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)ETHYL)PYRIDIN-2-AMINE'>W64</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" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=W64:4-METHYL-6-(2-(5-(4-METHYLPIPERAZIN-1-YL)PYRIDIN-3-YL)ETHYL)PYRIDIN-2-AMINE'>W64</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">[[5fvo|5fvo]], [[5fvp|5fvp]], [[5fvq|5fvq]], [[5fvr|5fvr]], [[5fvs|5fvs]], [[5fvt|5fvt]], [[5fvv|5fvv]], [[5fvw|5fvw]], [[5fvx|5fvx]], [[5fvy|5fvy]], [[5fvz|5fvz]], [[5fw0|5fw0]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5fvo|5fvo]], [[5fvp|5fvp]], [[5fvq|5fvq]], [[5fvr|5fvr]], [[5fvs|5fvs]], [[5fvt|5fvt]], [[5fvv|5fvv]], [[5fvw|5fvw]], [[5fvx|5fvx]], [[5fvy|5fvy]], [[5fvz|5fvz]], [[5fw0|5fw0]]</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:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5fvu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fvu OCA], [http://pdbe.org/5fvu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fvu RCSB], [http://www.ebi.ac.uk/pdbsum/5fvu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5fvu ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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</div> | </div> | ||
<div class="pdbe-citations 5fvu" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5fvu" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
| Line 25: | Line 28: | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | [[Category: Human]] | ||
[[Category: Large Structures]] | |||
[[Category: Li, H]] | [[Category: Li, H]] | ||
[[Category: Poulos, T L]] | [[Category: Poulos, T L]] | ||
[[Category: Nitric oxide synthase]] | [[Category: Nitric oxide synthase]] | ||
[[Category: Oxidoreductase]] | [[Category: Oxidoreductase]] | ||
Revision as of 10:39, 6 May 2020
Structure of human nNOS R354A G357D mutant heme domain in complex with 4-methyl-6-(2-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)ethyl) pyridin-2-amineStructure of human nNOS R354A G357D mutant heme domain in complex with 4-methyl-6-(2-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)ethyl) pyridin-2-amine
Structural highlights
Function[NOS1_HUMAN] Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR. Publication Abstract from PubMedNeuronal nitric oxide synthase (nNOS) is an important therapeutic target for the treatment of various neurodegenerative disorders. A major challenge in the design of nNOS inhibitors focuses on potency in humans and selectivity over other NOS isoforms. Here we report potent and selective human nNOS inhibitors based on the 2-aminopyridine scaffold with a central pyridine linker. Compound 14j, the most promising inhibitor in this study, exhibits excellent potency for rat nNOS (Ki = 16 nM) with 828-fold n/e and 118-fold n/i selectivity with a Ki value of 13 nM against human nNOS with 1761-fold human n/e selectivity. Compound 14j also displayed good metabolic stability in human liver microsomes, low plasma protein binding, and minimal binding to cytochromes P450 (CYPs), although it had little to no Caco-2 permeability. Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker.,Wang HY, Qin Y, Li H, Roman LJ, Martasek P, Poulos TL, Silverman RB J Med Chem. 2016 Apr 20. PMID:27050842[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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