View source for 8fgl


==Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 6-(2,3-difluoro-5-(2-(4-methylpiperazin-1-yl)ethyl)phenethyl)-4-methylpyridin-2-amine==
<StructureSection load='8fgl' size='340' side='right'caption='[[8fgl]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8fgl]] 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=8FGL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FGL FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=XVK:6-(2-{2,3-difluoro-5-[2-(4-methylpiperazin-1-yl)ethyl]phenyl}ethyl)-4-methylpyridin-2-amine'>XVK</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=8fgl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fgl OCA], [https://pdbe.org/8fgl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fgl RCSB], [https://www.ebi.ac.uk/pdbsum/8fgl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fgl ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/NOS1_HUMAN 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.
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== Publication Abstract from PubMed ==
A series of potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors (hnNOS), based on a difluorobenzene ring linked to a 2-aminopyridine scaffold with different functionalities at the 4-position, is reported. In our efforts to develop novel nNOS inhibitors for the treatment of neurodegenerative diseases, we discovered 17, which showed excellent potency toward both rat (K(i) 15 nM) and human nNOS (K(i) 19 nM), with 1075-fold selectivity over human eNOS and 115-fold selectivity over human iNOS. 17 also showed excellent permeability (P(e) = 13.7 x 10(-6) cm s(-1)), a low efflux ratio (ER 0.48), along with good metabolic stability in mouse and human liver microsomes, with half-lives of 29 and &gt;60 min, respectively. X-ray cocrystal structures of inhibitors bound with three NOS enzymes, namely, rat nNOS, human nNOS, and human eNOS, revealed detailed structure-activity relationships for the observed potency, selectivity, and permeability properties of the inhibitors.

Potent, Selective, and Membrane Permeable 2-Amino-4-Substituted Pyridine-Based Neuronal Nitric Oxide Synthase Inhibitors.,Vasu D, Do HT, Li H, Hardy CD, Awasthi A, Poulos TL, Silverman RB J Med Chem. 2023 Jul 27;66(14):9934-9953. doi: 10.1021/acs.jmedchem.3c00782. Epub , 2023 Jul 11. PMID:37433128<ref>PMID:37433128</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 8fgl" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Li H]]
[[Category: Poulos TL]]