View source for 6auy


==Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 4-Methyl-6-(3-(3-(methylamino)propyl)phenethyl)pyridin-2-amine==
<StructureSection load='6auy' size='340' side='right'caption='[[6auy]], [[Resolution|resolution]] 1.92&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6auy]] is a 2 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=6AUY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6AUY 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]] 1.92&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BYJ:4-methyl-6-(2-{3-[3-(methylamino)propyl]phenyl}ethyl)pyridin-2-amine'>BYJ</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6auy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6auy OCA], [https://pdbe.org/6auy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6auy RCSB], [https://www.ebi.ac.uk/pdbsum/6auy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6auy 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.
<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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6auy" style="background-color:#fffaf0;"></div>

==See Also==
*[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Li H]]
[[Category: Poulos TL]]