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==Structure of human endothelialnitric oxide synthase heme domain in complex with 7-(3-(Aminomethyl)-4-ethoxyphenyl)-4-methylquinolin-2-amine== | ==Structure of human endothelialnitric oxide synthase heme domain in complex with 7-(3-(Aminomethyl)-4-ethoxyphenyl)-4-methylquinolin-2-amine== | ||
<StructureSection load='6pox' size='340' side='right'caption='[[6pox]]' scene=''> | <StructureSection load='6pox' size='340' side='right'caption='[[6pox]], [[Resolution|resolution]] 2.20Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6POX OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6POX FirstGlance]. <br> | <table><tr><td colspan='2'>[[6pox]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6POX OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6POX FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6pox FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pox OCA], [http://pdbe.org/6pox PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pox RCSB], [http://www.ebi.ac.uk/pdbsum/6pox PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pox ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BTB:2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>BTB</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GD:GADOLINIUM+ATOM'>GD</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=OSJ:7-[3-(aminomethyl)-4-ethoxyphenyl]-4-methylquinolin-2-amine'>OSJ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NOS3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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://proteopedia.org/fgij/fg.htm?mol=6pox FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pox OCA], [http://pdbe.org/6pox PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pox RCSB], [http://www.ebi.ac.uk/pdbsum/6pox PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pox ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[http://www.uniprot.org/uniprot/NOS3_HUMAN NOS3_HUMAN]] 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.<ref>PMID:17264164</ref> Isoform eNOS13C: Lacks eNOS activity, dominant-negative form that may down-regulate eNOS activity by forming heterodimers with isoform 1.<ref>PMID:17264164</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Inhibition of neuronal nitric oxide synthase (nNOS), an enzyme implicated in neurodegenerative disorders, is an attractive strategy for treating or preventing these diseases. We previously developed several classes of 2-aminoquinoline-based nNOS inhibitors, but these compounds had drawbacks including off-target promiscuity, low activity against human nNOS, and only modest selectivity for nNOS over related enzymes. In this study, we synthesized new nNOS inhibitors based on 7-phenyl-2-aminoquinoline and assayed them against rat and human nNOS, human eNOS, and murine and (in some cases) human iNOS. Compounds with a meta-relationship between the aminoquinoline and a positively charged tail moiety were potent and had up to nearly 900-fold selectivity for human nNOS over human eNOS. X-ray crystallography indicates that the amino groups of some compounds occupy a water-filled pocket surrounding an nNOS-specific aspartate residue (absent in eNOS). This interaction was confirmed by mutagenesis studies, making 7-phenyl-2-aminoquinolines the first aminoquinolines to interact with this residue. | |||
First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate.,Cinelli MA, Reidl CT, Li H, Chreifi G, Poulos TL, Silverman RB J Med Chem. 2020 Apr 17. doi: 10.1021/acs.jmedchem.9b01573. PMID:32302123<ref>PMID:32302123</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6pox" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Chreifi G]] | [[Category: Chreifi, G]] | ||
[[Category: Li H]] | [[Category: Li, H]] | ||
[[Category: Poulos | [[Category: Poulos, T L]] | ||
[[Category: Heme enzyme]] | |||
[[Category: Nitric oxide synthase inhibitor]] | |||
[[Category: Oxidoreductase]] | |||
[[Category: Oxidoreductase-inhibitor complex]] | |||
Revision as of 10:23, 27 May 2020
Structure of human endothelialnitric oxide synthase heme domain in complex with 7-(3-(Aminomethyl)-4-ethoxyphenyl)-4-methylquinolin-2-amineStructure of human endothelialnitric oxide synthase heme domain in complex with 7-(3-(Aminomethyl)-4-ethoxyphenyl)-4-methylquinolin-2-amine
Structural highlights
Function[NOS3_HUMAN] 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.[1] Isoform eNOS13C: Lacks eNOS activity, dominant-negative form that may down-regulate eNOS activity by forming heterodimers with isoform 1.[2] Publication Abstract from PubMedInhibition of neuronal nitric oxide synthase (nNOS), an enzyme implicated in neurodegenerative disorders, is an attractive strategy for treating or preventing these diseases. We previously developed several classes of 2-aminoquinoline-based nNOS inhibitors, but these compounds had drawbacks including off-target promiscuity, low activity against human nNOS, and only modest selectivity for nNOS over related enzymes. In this study, we synthesized new nNOS inhibitors based on 7-phenyl-2-aminoquinoline and assayed them against rat and human nNOS, human eNOS, and murine and (in some cases) human iNOS. Compounds with a meta-relationship between the aminoquinoline and a positively charged tail moiety were potent and had up to nearly 900-fold selectivity for human nNOS over human eNOS. X-ray crystallography indicates that the amino groups of some compounds occupy a water-filled pocket surrounding an nNOS-specific aspartate residue (absent in eNOS). This interaction was confirmed by mutagenesis studies, making 7-phenyl-2-aminoquinolines the first aminoquinolines to interact with this residue. First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate.,Cinelli MA, Reidl CT, Li H, Chreifi G, Poulos TL, Silverman RB J Med Chem. 2020 Apr 17. doi: 10.1021/acs.jmedchem.9b01573. PMID:32302123[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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