View source for 5vv3


==Structure of human neuronal nitric oxide synthase heme domain in complex with 4-(2-(((2-Aminoquinolin-7-yl)methyl)amino)ethyl)benzonitrile==
<StructureSection load='5vv3' size='340' side='right'caption='[[5vv3]], [[Resolution|resolution]] 2.18&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5vv3]] 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=5VV3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5VV3 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]] 2.18&#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=P94:4-(2-{[(2-aminoquinolin-7-yl)methyl]amino}ethyl)benzonitrile'>P94</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=5vv3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vv3 OCA], [https://pdbe.org/5vv3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5vv3 RCSB], [https://www.ebi.ac.uk/pdbsum/5vv3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5vv3 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 ==
Neuronal nitric oxide synthase (nNOS) is a target for development of antineurodegenerative agents. Most nNOS inhibitors mimic l-arginine and have poor bioavailability. 2-Aminoquinolines showed promise as bioavailable nNOS inhibitors but suffered from low human nNOS inhibition, low selectivity versus human eNOS, and significant binding to other CNS targets. We aimed to improve human nNOS potency and selectivity and reduce off-target binding by (a) truncating the original scaffold or (b) introducing a hydrophilic group to interrupt the lipophilic, promiscuous pharmacophore and promote interaction with human nNOS-specific His342. We synthesized both truncated and polar 2-aminoquinoline derivatives and assayed them against recombinant NOS enzymes. Although aniline and pyridine derivatives interact with His342, benzonitriles conferred the best rat and human nNOS inhibition. Both introduction of a hydrophobic substituent next to the cyano group and aminoquinoline methylation considerably improved isoform selectivity. Most importantly, these modifications preserved Caco-2 permeability and reduced off-target CNS binding.

Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors.,Pensa AV, Cinelli MA, Li H, Chreifi G, Mukherjee P, Roman LJ, Martasek P, Poulos TL, Silverman RB J Med Chem. 2017 Aug 4. doi: 10.1021/acs.jmedchem.7b00835. PMID:28776992<ref>PMID:28776992</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 5vv3" style="background-color:#fffaf0;"></div>

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