4uh9: Difference between revisions
New page: '''Unreleased structure''' The entry 4uh9 is ON HOLD until Paper Publication Authors: Li, H., Poulos, T.L. Description: Structure of bovine endothelial nitric oxide synthase heme domai... |
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==Structure of bovine endothelial nitric oxide synthase heme domain in complex with N1-(3-(2-(6-Amino-4-methylpyridin-2-yl)ethyl)-5- fluorophenyl)-N1,N2-dimethylethane-1,2-diamine== | |||
<StructureSection load='4uh9' size='340' side='right'caption='[[4uh9]], [[Resolution|resolution]] 2.14Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4uh9]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UH9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4UH9 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]] 2.14Å</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=CAS:S-(DIMETHYLARSENIC)CYSTEINE'>CAS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=S85:N1-(3-(2-(6-AMINO-4-METHYLPYRIDIN-2-YL)ETHYL)-5-FLUOROPHENYL)-N1,N2-DIMETHYLETHANE-1,2-DIAMINE'>S85</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=4uh9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4uh9 OCA], [https://pdbe.org/4uh9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4uh9 RCSB], [https://www.ebi.ac.uk/pdbsum/4uh9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4uh9 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/NOS3_BOVIN NOS3_BOVIN] Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets. | |||
<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. | |||
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> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 4uh9" style="background-color:#fffaf0;"></div> | ||
[[Category: Li | |||
==See Also== | |||
*[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Bos taurus]] | |||
[[Category: Large Structures]] | |||
[[Category: Li H]] | |||
[[Category: Poulos TL]] | |||
Latest revision as of 11:29, 23 October 2024
Structure of bovine endothelial nitric oxide synthase heme domain in complex with N1-(3-(2-(6-Amino-4-methylpyridin-2-yl)ethyl)-5- fluorophenyl)-N1,N2-dimethylethane-1,2-diamineStructure of bovine endothelial nitric oxide synthase heme domain in complex with N1-(3-(2-(6-Amino-4-methylpyridin-2-yl)ethyl)-5- fluorophenyl)-N1,N2-dimethylethane-1,2-diamine
Structural highlights
FunctionNOS3_BOVIN Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets. Publication Abstract from PubMedWe 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. See AlsoReferences
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