4uh4: Difference between revisions

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'''Unreleased structure'''
==Structure of rat neuronal nitric oxide synthase heme domain in complex with 3-(2-(6-Amino-4-methylpyridin-2-yl)ethyl)-5-(methyl(2-(methylamino)ethyl)amino)benzonitrile==
<StructureSection load='4uh4' size='340' side='right' caption='[[4uh4]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4uh4]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UH4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4UH4 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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=Q1T:3-(2-(6-AMINO-4-METHYLPYRIDIN-2-YL)ETHYL)-5-(METHYL(2-(METHYLAMINO)ETHYL)AMINO)BENZONITRILE'>Q1T</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">[[4ugz|4ugz]], [[4uh0|4uh0]], [[4uh1|4uh1]], [[4uh2|4uh2]], [[4uh3|4uh3]], [[4uh5|4uh5]], [[4uh6|4uh6]], [[4uh7|4uh7]], [[4uh8|4uh8]], [[4uh9|4uh9]], [[4uha|4uha]]</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=4uh4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4uh4 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4uh4 RCSB], [http://www.ebi.ac.uk/pdbsum/4uh4 PDBsum]</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 ==
We have analyzed a recently obtained crystal structure of human neuronal nitric oxide synthase (nNOS) and then designed and synthesized several 2-aminopyridine derivatives containing a truncated side chain to avoid the hydrophobic pocket that differentiates human and rat nNOS in an attempt to explore alternative binding poses along the substrate access channel of human nNOS. Introduction of an N-methylethane-1,2-diamine side chain and conformational constraints such as benzonitrile and pyridine as the middle aromatic linker were sufficient to increase human and rat nNOS binding affinity and inducible and endothelial NOS selectivity. We found that 14b is a potent inhibitor; the binding modes with human and rat nNOS are unexpected, inducing side chain rotamer changes in Gln478 (rat) at the top of the active site. Compound 19c exhibits Ki values of 24 and 55 nM for rat and human nNOS, respectively, with 153-fold iNOS and 1040-fold eNOS selectivity. 19c has 18% oral bioavailability.


The entry 4uh4 is ON HOLD  until Paper Publication
2-Aminopyridines with a Truncated Side Chain To Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity.,Kang S, Li H, Tang W, Martasek P, Roman LJ, Poulos TL, Silverman RB J Med Chem. 2015 Jul 10. PMID:26120733<ref>PMID:26120733</ref>


Authors: Li, H., Poulos, T.L.
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 
</div>
Description: Structure of rat neuronal nitric oxide synthase heme domain in complex with 3-(2-(6-Amino-4-methylpyridin-2-yl)ethyl)-5-(methyl(2-( methylamino)ethyl)amino)benzonitrile
== References ==
[[Category: Unreleased Structures]]
<references/>
[[Category: Poulos, T.L]]
__TOC__
</StructureSection>
[[Category: Li, H]]
[[Category: Li, H]]
[[Category: Poulos, T L]]
[[Category: Inhibitor complex]]
[[Category: Nitric oxide synthase]]
[[Category: Oxidoreductase]]

Revision as of 16:20, 15 July 2015

Structure of rat neuronal nitric oxide synthase heme domain in complex with 3-(2-(6-Amino-4-methylpyridin-2-yl)ethyl)-5-(methyl(2-(methylamino)ethyl)amino)benzonitrileStructure of rat neuronal nitric oxide synthase heme domain in complex with 3-(2-(6-Amino-4-methylpyridin-2-yl)ethyl)-5-(methyl(2-(methylamino)ethyl)amino)benzonitrile

Structural highlights

4uh4 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, , , ,
Activity:Nitric-oxide synthase (NADPH dependent), with EC number 1.14.13.39
Resources:FirstGlance, OCA, RCSB, PDBsum

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 PubMed

We have analyzed a recently obtained crystal structure of human neuronal nitric oxide synthase (nNOS) and then designed and synthesized several 2-aminopyridine derivatives containing a truncated side chain to avoid the hydrophobic pocket that differentiates human and rat nNOS in an attempt to explore alternative binding poses along the substrate access channel of human nNOS. Introduction of an N-methylethane-1,2-diamine side chain and conformational constraints such as benzonitrile and pyridine as the middle aromatic linker were sufficient to increase human and rat nNOS binding affinity and inducible and endothelial NOS selectivity. We found that 14b is a potent inhibitor; the binding modes with human and rat nNOS are unexpected, inducing side chain rotamer changes in Gln478 (rat) at the top of the active site. Compound 19c exhibits Ki values of 24 and 55 nM for rat and human nNOS, respectively, with 153-fold iNOS and 1040-fold eNOS selectivity. 19c has 18% oral bioavailability.

2-Aminopyridines with a Truncated Side Chain To Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity.,Kang S, Li H, Tang W, Martasek P, Roman LJ, Poulos TL, Silverman RB J Med Chem. 2015 Jul 10. PMID:26120733[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Kang S, Li H, Tang W, Martasek P, Roman LJ, Poulos TL, Silverman RB. 2-Aminopyridines with a Truncated Side Chain To Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity. J Med Chem. 2015 Jul 10. PMID:26120733 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00573

4uh4, resolution 1.95Å

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