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==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]] 1.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5uns]] is a 2 chain structure. 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='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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5uns" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Li, H]] | [[Category: Li, H]] | ||
[[Category: Poulos, T | [[Category: Poulos, T L]] | ||
[[Category: Heme enzyme]] | |||
[[Category: Inhibitor complex]] | |||
[[Category: Nitric oxide synthase]] | |||
[[Category: Oxidoreductase-oxidoreductase inhibitor complex]] | |||
Revision as of 16:05, 4 May 2017
Structure of rat neuronal nitric oxide synthase heme domain in complex with 7-[(3-Ethyl-5-((methylamino)methyl)phenoxy)methyl]quinolin-2-amineStructure of rat neuronal nitric oxide synthase heme domain in complex with 7-[(3-Ethyl-5-((methylamino)methyl)phenoxy)methyl]quinolin-2-amine
Structural highlights
Function[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. Publication Abstract from PubMedNeuronal 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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