View source for 5uns


==Structure of rat neuronal nitric oxide synthase heme domain in complex with 7-[(3-Ethyl-5-((methylamino)methyl)phenoxy)methyl]quinolin-2-amine==
<StructureSection load='5uns' size='340' side='right'caption='[[5uns]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5uns]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UNS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UNS FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8J4:7-({3-ETHYL-5-[(METHYLAMINO)METHYL]PHENOXY}METHYL)QUINOLIN-2-AMINE'>8J4</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5unr|5unr]], [[5unu|5unu]], [[5unx|5unx]], [[5unw|5unw]], [[5uo1|5uo1]], [[5uny|5uny]], [[5uo3|5uo3]], [[5uo5|5uo5]], [[5uo4|5uo4]], [[5uo6|5uo6]], [[5uo7|5uo7]], [[5uo8|5uo8]], [[5uo2|5uo2]], [[5unz|5unz]], [[5uo0|5uo0]], [[5unt|5unt]], [[5unv|5unv]], [[5uod|5uod]], [[5uo9|5uo9]], [[5uoa|5uoa]], [[5uob|5uob]], [[5uoc|5uoc]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Nos1, Bnos ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5uns FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uns OCA], [http://pdbe.org/5uns PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5uns RCSB], [http://www.ebi.ac.uk/pdbsum/5uns PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5uns ProSAT]</span></td></tr>
</table>
== Function ==
[[http://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. 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Neuronal nitric oxide synthase (nNOS) inhibition is a promising strategy to treat neurodegenerative disorders, but the development of nNOS inhibitors is often hindered by poor pharmacokinetics. We previously developed a class of membrane-permeable 2-aminoquinoline inhibitors and later rearranged the scaffold to decrease off-target binding. However, the resulting compounds had decreased permeability, low human nNOS activity, and low selectivity versus human eNOS. In this study, 5-substituted phenyl ether-linked aminoquinolines and derivatives were synthesized and assayed against purified NOS isoforms. 5-Cyano compounds are especially potent and selective rat and human nNOS inhibitors. Activity and selectivity are mediated by the binding of the cyano group to a new auxiliary pocket in nNOS. Potency was enhanced by methylation of the quinoline and by introduction of simple chiral moieties, resulting in a combination of hydrophobic and auxiliary pocket effects that yielded high ( approximately 500-fold) n/e selectivity. Importantly, the Caco-2 assay also revealed improved membrane permeability over previous compounds.

Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors.,Cinelli MA, Li H, Chreifi G, Poulos TL, Silverman RB J Med Chem. 2017 Apr 19. doi: 10.1021/acs.jmedchem.7b00259. PMID:28422508<ref>PMID:28422508</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5uns" style="background-color:#fffaf0;"></div>

==See Also==
*[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Buffalo rat]]
[[Category: Large Structures]]
[[Category: Li, H]]
[[Category: Poulos, T L]]
[[Category: Heme enzyme]]
[[Category: Inhibitor complex]]
[[Category: Nitric oxide synthase]]
[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]