4k5k: Difference between revisions
New page: '''Unreleased structure''' The entry 4k5k is ON HOLD Authors: Li, H., Poulos, T.L. Description: Structure of bovine endothelial nitric oxide synthase heme domain in complex with ((2S, ... |
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The | ==Structure of bovine endothelial nitric oxide synthase heme domain in complex with ((2S, 3S)-1,3-bis((6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridin-2-yl)methoxy)-2-aminobutane== | ||
<StructureSection load='4k5k' size='340' side='right'caption='[[4k5k]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4k5k]] 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=4K5K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4K5K 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]] 2Å</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=Q13:6,6-{[(2S,3S)-2-AMINOBUTANE-1,3-DIYL]BIS(OXYMETHANEDIYL)}BIS(4-METHYLPYRIDIN-2-AMINE)'>Q13</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=4k5k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k5k OCA], [https://pdbe.org/4k5k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4k5k RCSB], [https://www.ebi.ac.uk/pdbsum/4k5k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4k5k 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 == | |||
To develop potent and selective nNOS inhibitors, new double-headed molecules with chiral linkers that derive from natural amino acids or their derivatives have been designed. The new structures contain two ether bonds, which greatly simplifies the synthesis and accelerates structure optimization. Inhibitor (R)-6b exhibits a potency of 32nM against nNOS and is 475 and 244 more selective for nNOS over eNOS and iNOS, respectively. Crystal structures show that the additional binding between the aminomethyl moiety of 6b and the two heme propionates in nNOS, but not eNOS, is the structural basis for its high selectivity. This work demonstrates the importance of stereochemistry in this class of molecules, which significantly influences the potency and selectivity of the inhibitors. The structure-activity information gathered here provides a guide for future structure optimization. | |||
Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors.,Jing Q, Li H, Chreifi G, Roman LJ, Martasek P, Poulos TL, Silverman RB Bioorg Med Chem Lett. 2013 Oct 15;23(20):5674-9. doi: 10.1016/j.bmcl.2013.08.034., Epub 2013 Aug 14. PMID:23993333<ref>PMID:23993333</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4k5k" style="background-color:#fffaf0;"></div> | |||
==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 18:54, 20 September 2023
Structure of bovine endothelial nitric oxide synthase heme domain in complex with ((2S, 3S)-1,3-bis((6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridin-2-yl)methoxy)-2-aminobutaneStructure of bovine endothelial nitric oxide synthase heme domain in complex with ((2S, 3S)-1,3-bis((6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridin-2-yl)methoxy)-2-aminobutane
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 PubMedTo develop potent and selective nNOS inhibitors, new double-headed molecules with chiral linkers that derive from natural amino acids or their derivatives have been designed. The new structures contain two ether bonds, which greatly simplifies the synthesis and accelerates structure optimization. Inhibitor (R)-6b exhibits a potency of 32nM against nNOS and is 475 and 244 more selective for nNOS over eNOS and iNOS, respectively. Crystal structures show that the additional binding between the aminomethyl moiety of 6b and the two heme propionates in nNOS, but not eNOS, is the structural basis for its high selectivity. This work demonstrates the importance of stereochemistry in this class of molecules, which significantly influences the potency and selectivity of the inhibitors. The structure-activity information gathered here provides a guide for future structure optimization. Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors.,Jing Q, Li H, Chreifi G, Roman LJ, Martasek P, Poulos TL, Silverman RB Bioorg Med Chem Lett. 2013 Oct 15;23(20):5674-9. doi: 10.1016/j.bmcl.2013.08.034., Epub 2013 Aug 14. PMID:23993333[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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