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==Structure of rat neuronal nitric oxide synthase heme domain in complex with (RS)-3-[(2-amino-4-methylquinolin-7-yl)methoxy]-5-(2-(methylamino)propyl)benzonitrile==
==Structure of rat neuronal nitric oxide synthase heme domain in complex with (RS)-3-[(2-amino-4-methylquinolin-7-yl)methoxy]-5-(2-(methylamino)propyl)benzonitrile==
<StructureSection load='5uny' size='340' side='right' caption='[[5uny]], [[Resolution|resolution]] 1.82&Aring;' scene=''>
<StructureSection load='5uny' size='340' side='right'caption='[[5uny]], [[Resolution|resolution]] 1.82&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5uny]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UNY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UNY FirstGlance]. <br>
<table><tr><td colspan='2'>[[5uny]] is a 2 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=5UNY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UNY FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8FD:3-[(2-AMINO-4-METHYLQUINOLIN-7-YL)METHOXY]-5-[(2S)-2-(METHYLAMINO)PROPYL]BENZONITRILE'>8FD</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=M4R:3-[(2-AMINO-4-METHYLQUINOLIN-7-YL)METHOXY]-5-[(2R)-2-(METHYLAMINO)PROPYL]BENZONITRILE'>M4R</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.82&#8491;</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]], [[5uo3|5uo3]], [[5uo5|5uo5]], [[5uo4|5uo4]], [[5uo6|5uo6]], [[5uo7|5uo7]], [[5uo8|5uo8]], [[5uo2|5uo2]], [[5uns|5uns]], [[5unz|5unz]], [[5uo0|5uo0]], [[5unt|5unt]], [[5unv|5unv]], [[5uod|5uod]], [[5uo9|5uo9]], [[5uoa|5uoa]], [[5uob|5uob]], [[5uoc|5uoc]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8FD:3-[(2-AMINO-4-METHYLQUINOLIN-7-YL)METHOXY]-5-[(2S)-2-(METHYLAMINO)PROPYL]BENZONITRILE'>8FD</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=M4R:3-[(2-AMINO-4-METHYLQUINOLIN-7-YL)METHOXY]-5-[(2R)-2-(METHYLAMINO)PROPYL]BENZONITRILE'>M4R</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=5uny FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uny OCA], [https://pdbe.org/5uny PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5uny RCSB], [https://www.ebi.ac.uk/pdbsum/5uny PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5uny ProSAT]</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=5uny FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uny OCA], [http://pdbe.org/5uny PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5uny RCSB], [http://www.ebi.ac.uk/pdbsum/5uny PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5uny ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== 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.  
[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.
<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 5uny" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Nitric Oxide Synthase|Nitric Oxide Synthase]]
*[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Li, H]]
[[Category: Large Structures]]
[[Category: Poulos, T L]]
[[Category: Rattus norvegicus]]
[[Category: Complex]]
[[Category: Li H]]
[[Category: Enzyme]]
[[Category: Poulos TL]]
[[Category: Heme]]
[[Category: Inhibitor]]
[[Category: Nitric]]
[[Category: Oxide]]
[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
[[Category: Synthase]]

Latest revision as of 17:28, 6 March 2024

Structure of rat neuronal nitric oxide synthase heme domain in complex with (RS)-3-[(2-amino-4-methylquinolin-7-yl)methoxy]-5-(2-(methylamino)propyl)benzonitrileStructure of rat neuronal nitric oxide synthase heme domain in complex with (RS)-3-[(2-amino-4-methylquinolin-7-yl)methoxy]-5-(2-(methylamino)propyl)benzonitrile

Structural highlights

5uny is a 2 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.82Å
Ligands:, , , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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.

See Also

5uny, resolution 1.82Å

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