4ctr: Difference between revisions
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''' | ==Structure of rat neuronal nitric oxide synthase heme domain in complex with 2-(6-Amino-4-methylpyridin-2-yl)-1-(3-(2-(6-amino-4- methylpyridin-2-yl)ethyl )phenyl)ethan-1-ol== | ||
<StructureSection load='4ctr' size='340' side='right' caption='[[4ctr]], [[Resolution|resolution]] 2.20Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4ctr]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CTR OCA]. <br> | |||
</td></tr><tr><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=S20:(1S)-2-(6-AMINO-4-METHYLPYRIDIN-2-YL)-1-{3-[2-(6-AMINO-4-METHYLPYRIDIN-2-YL)ETHYL]PHENYL}ETHANOL'>S20</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene><br> | |||
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ctp|4ctp]], [[4ctq|4ctq]], [[4ctt|4ctt]], [[4ctu|4ctu]], [[4ctv|4ctv]], [[4ctw|4ctw]], [[4ctx|4ctx]], [[4cty|4cty]], [[4ctz|4ctz]], [[4cu0|4cu0]], [[4cu1|4cu1]]</td></tr> | |||
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span></td></tr> | |||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ctr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ctr OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ctr RCSB], [http://www.ebi.ac.uk/pdbsum/4ctr PDBsum]</span></td></tr> | |||
<table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Overproduction of NO by nNOS is implicated in the pathogenesis of diverse neuronal disorders. Since NO signaling is involved in diverse physiological functions, selective inhibition of nNOS over other isoforms is essential to minimize side effects. A series of alpha-amino functionalized aminopyridine derivatives (3 - 8) were designed to probe the structure-activity relationship between ligand, heme propionate, and H4B. Compound 8R was identified as the most potent and selective molecule of this study, exhibiting a Ki of 24 nM for nNOS, with 273-fold and 2822-fold selectivity against iNOS and eNOS, respectively. Although crystal structures of 8R complexed with nNOS and eNOS revealed a similar binding mode, the selectivity stems from the distinct electrostatic environments in two isoforms that result in much lower inhibitor binding free energy in nNOS than in eNOS. These findings provide a basis for further development of simple, but even more selective and potent, nNOS inhibitors. | |||
Nitric Oxide Synthase Inhibitors that Interact with both a Heme Propionate and Tetrahydrobiopterin Show High Isoform Selectivity.,Kang S, Tang W, Li H, Chreifi G, Martasek P, Roman LJ, Poulos TL, Silverman RB J Med Chem. 2014 Apr 23. PMID:24758147<ref>PMID:24758147</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Li, H.]] | |||
[[Category: Poulos, T L.]] | |||
[[Category: Inhibitor complex]] | |||
[[Category: Oxidoreductase]] | |||
Revision as of 11:13, 7 May 2014
Structure of rat neuronal nitric oxide synthase heme domain in complex with 2-(6-Amino-4-methylpyridin-2-yl)-1-(3-(2-(6-amino-4- methylpyridin-2-yl)ethyl )phenyl)ethan-1-olStructure of rat neuronal nitric oxide synthase heme domain in complex with 2-(6-Amino-4-methylpyridin-2-yl)-1-(3-(2-(6-amino-4- methylpyridin-2-yl)ethyl )phenyl)ethan-1-ol
Structural highlights
Publication Abstract from PubMedOverproduction of NO by nNOS is implicated in the pathogenesis of diverse neuronal disorders. Since NO signaling is involved in diverse physiological functions, selective inhibition of nNOS over other isoforms is essential to minimize side effects. A series of alpha-amino functionalized aminopyridine derivatives (3 - 8) were designed to probe the structure-activity relationship between ligand, heme propionate, and H4B. Compound 8R was identified as the most potent and selective molecule of this study, exhibiting a Ki of 24 nM for nNOS, with 273-fold and 2822-fold selectivity against iNOS and eNOS, respectively. Although crystal structures of 8R complexed with nNOS and eNOS revealed a similar binding mode, the selectivity stems from the distinct electrostatic environments in two isoforms that result in much lower inhibitor binding free energy in nNOS than in eNOS. These findings provide a basis for further development of simple, but even more selective and potent, nNOS inhibitors. Nitric Oxide Synthase Inhibitors that Interact with both a Heme Propionate and Tetrahydrobiopterin Show High Isoform Selectivity.,Kang S, Tang W, Li H, Chreifi G, Martasek P, Roman LJ, Poulos TL, Silverman RB J Med Chem. 2014 Apr 23. PMID:24758147[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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