4d30: Difference between revisions
New page: '''Unreleased structure''' The entry 4d30 is ON HOLD Authors: Li, H., Poulos, T.L. Description: Structure of rat neuronal nitric oxide synthase heme domain in complex with N-2-(2-(1H-i... |
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==Structure of rat neuronal nitric oxide synthase heme domain in complex with N-2-(2-(1H-imidazol-1-yl)pyrimidin-4-yl)ethyl-3-(pyridin- 3-yl)propan-1-amine== | |||
<StructureSection load='4d30' size='340' side='right'caption='[[4d30]], [[Resolution|resolution]] 1.96Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4d30]] 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=4D30 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4D30 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]] 1.962Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=EG8:N-{2-[2-(1H-IMIDAZOL-1-YL)PYRIMIDIN-4-YL]ETHYL}-3-(PYRIDIN-3-YL)PROPAN-1-AMINE'>EG8</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4d30 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d30 OCA], [https://pdbe.org/4d30 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4d30 RCSB], [https://www.ebi.ac.uk/pdbsum/4d30 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4d30 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[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 == | |||
Selective inhibition of neuronal nitric oxide synthase (nNOS) is an important therapeutic approach to target neurodegenerative disorders. However, the majority of the nNOS inhibitors developed are arginine mimetics and, therefore, suffer from poor bioavailability. We designed a novel strategy to combine a more pharmacokinetically favorable 2-imidazolylpyrimidine head with promising structural components from previous inhibitors. In conjunction with extensive structure-activity studies, several highly potent and selective inhibitors of nNOS were discovered. X-ray crystallographic analysis reveals that these type II inhibitors utilize the same hydrophobic pocket to gain strong inhibitory potency (13), as well as high isoform selectivity. Interestingly, select compounds from this series (9) showed good permeability and low efflux in a Caco-2 assay, suggesting potential oral bioavailability, and exhibited minimal off-target binding to 50 central nervous system receptors. Furthermore, even with heme-coordinating groups in the molecule, modifying other pharmacophoric fragments minimized undesirable inhibition of cytochrome P450s from human liver microsomes. | |||
Novel 2,4-Disubstituted Pyrimidines as Potent, Selective, and Cell-permeable Inhibitors of Neuronal Nitric Oxide Synthase.,Mukherjee P, Li H, Sevrioukova IF, Chreifi G, Martasek P, Roman LJ, Poulos TL, Silverman RB J Med Chem. 2014 Dec 9. PMID:25489882<ref>PMID:25489882</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4d30" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Rattus norvegicus]] | |||
[[Category: Li H]] | |||
[[Category: Poulos TL]] | |||
Latest revision as of 14:17, 9 May 2024
Structure of rat neuronal nitric oxide synthase heme domain in complex with N-2-(2-(1H-imidazol-1-yl)pyrimidin-4-yl)ethyl-3-(pyridin- 3-yl)propan-1-amineStructure of rat neuronal nitric oxide synthase heme domain in complex with N-2-(2-(1H-imidazol-1-yl)pyrimidin-4-yl)ethyl-3-(pyridin- 3-yl)propan-1-amine
Structural highlights
FunctionNOS1_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 PubMedSelective inhibition of neuronal nitric oxide synthase (nNOS) is an important therapeutic approach to target neurodegenerative disorders. However, the majority of the nNOS inhibitors developed are arginine mimetics and, therefore, suffer from poor bioavailability. We designed a novel strategy to combine a more pharmacokinetically favorable 2-imidazolylpyrimidine head with promising structural components from previous inhibitors. In conjunction with extensive structure-activity studies, several highly potent and selective inhibitors of nNOS were discovered. X-ray crystallographic analysis reveals that these type II inhibitors utilize the same hydrophobic pocket to gain strong inhibitory potency (13), as well as high isoform selectivity. Interestingly, select compounds from this series (9) showed good permeability and low efflux in a Caco-2 assay, suggesting potential oral bioavailability, and exhibited minimal off-target binding to 50 central nervous system receptors. Furthermore, even with heme-coordinating groups in the molecule, modifying other pharmacophoric fragments minimized undesirable inhibition of cytochrome P450s from human liver microsomes. Novel 2,4-Disubstituted Pyrimidines as Potent, Selective, and Cell-permeable Inhibitors of Neuronal Nitric Oxide Synthase.,Mukherjee P, Li H, Sevrioukova IF, Chreifi G, Martasek P, Roman LJ, Poulos TL, Silverman RB J Med Chem. 2014 Dec 9. PMID:25489882[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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