View source for 9cvp


==Structure of rat neuronal nitric oxide synthase R349A mutant bound with 6-(2,3-difluoro-5-(((2-fluoroethyl)amino)methyl)phenyl)-4-methylpyridin-2-amine dihydrochloride==
<StructureSection load='9cvp' size='340' side='right'caption='[[9cvp]], [[Resolution|resolution]] 1.97&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9cvp]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9CVP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9CVP 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]] 1.97&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1AZ9:6-[2,3-bis(fluoranyl)-5-[(2-fluoranylethylamino)methyl]phenyl]-4-methyl-pyridin-2-amine'>A1AZ9</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=9cvp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9cvp OCA], [https://pdbe.org/9cvp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9cvp RCSB], [https://www.ebi.ac.uk/pdbsum/9cvp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9cvp ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/NOS1_RAT NOS1_RAT] 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. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum.
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== Publication Abstract from PubMed ==
Neuronal nitric oxide synthase (nNOS) is a promising target for addressing various neurological disorders and melanoma. Our discovery of a series of truncated pyridinylbenzylamines has yielded potent, selective, and membrane permeable inhibitors of human neuronal nitric oxide synthase. By implementing an efficient synthetic procedure using the Suzuki-Miyaura cross-coupling reaction, we were able to rapidly identify a potent inhibitor. This new inhibitor (18, 6-(2,3-difluoro-5-((methylamino)methyl)phenyl)-4-methylpyridin-2-amine dihydrochloride) exhibits excellent potency, with K(i) values of 30 nM for human nNOS and 40 nM for rat nNOS. It also demonstrates high isoform selectivity, showing an 821-fold preference for human nNOS over human endothelial NOS (eNOS) and a 75-fold selectivity over human inducible NOS (iNOS). Additionally, inhibitor 18 displays high permeability (P(e) = 10.7 x 10(-6) cm s(-1)) in an artificial membrane permeability assay. The crystal structures of several NOS-inhibitor complexes provide valuable structural insights into the potency and selectivity of this series of novel inhibitors. A particularly notable finding is the unexpected role of a Cl(-) anion bound to heNOS, which contributes to the high isoform selectivity of these inhibitors and explains why heNOS binds Cl(-), while hnNOS does not. This unique Cl(-) binding site could be important in future inhibitor design, opening new avenues for the development of more selective NOS inhibitors. Additionally, the presented crystal structures reveal the key factors required to maintain both high potency and selectivity in the simplified inhibitors discussed in this study. Abbreviations: NO, nitric oxide; nNOS, neuronal nitric oxide synthase; iNOS, inducible nitric oxide synthase; eNOS, endothelial nitric oxide synthase; rnNOS, rat neuronal nitric oxide synthase; hnNOS, human neuronal nitric oxide synthase; hiNOS, human inducible nitric oxide synthase; heNOS, human endothelial nitric oxide synthase; l-Arg, l-arginine; NADPH, reduced nicotinamide adenine dinucleotide phosphate; CaM, calmodulin; H(4)B, (6R)-5,6,7,8-tetrahydrobiopterin; FAD, flavin adenine dinucleotide; FMN, Flavin mononucleotide, BBB, blood-brain barrier; CNS, central nervous system; PAMPA, parallel artificial membrane permeability assay; P-gp, P-glycoprotein; ER, efflux ratio; P(e), effective permeability; P(app), apparent permeability; Caco-2, cancer coli-2; TLC, thin layer chromatography; TBAF, tetra-n-butylammonium fluoride; TFA, trifluoroacetic acid.

Truncated pyridinylbenzylamines: Potent, selective, and highly membrane permeable inhibitors of human neuronal nitric oxide synthase.,Vasu D, Do HT, Li H, Hardy CD, Poulos TL, Silverman RB Bioorg Med Chem. 2025 Jul 1;124:118193. doi: 10.1016/j.bmc.2025.118193. Epub 2025 , Apr 10. PMID:40252563<ref>PMID:40252563</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 9cvp" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Rattus norvegicus]]
[[Category: Li H]]
[[Category: Poulos TL]]