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3n5t

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==Structure of endothelial nitric oxide synthase heme domain complexed with 6,6'-(2,2'-(pyridine-3,5-diyl)bis(ethane-2,1-diyl))bis(4-methylpyridin-2-amine)==
==Structure of endothelial nitric oxide synthase heme domain complexed with 6,6'-(2,2'-(pyridine-3,5-diyl)bis(ethane-2,1-diyl))bis(4-methylpyridin-2-amine)==
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<StructureSection load='3n5t' size='340' side='right' caption='[[3n5t]], [[Resolution|resolution]] 2.52&Aring;' scene=''>
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<StructureSection load='3n5t' size='340' side='right'caption='[[3n5t]], [[Resolution|resolution]] 2.52&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3n5t]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3N5T OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3N5T FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3n5t]] 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=3N5T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3N5T FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CAD:CACODYLIC+ACID'>CAD</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=XFJ:6,6-(PYRIDINE-3,5-DIYLDIETHANE-2,1-DIYL)BIS(4-METHYLPYRIDIN-2-AMINE)'>XFJ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.52&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3n5p|3n5p]], [[3n5q|3n5q]], [[3n5r|3n5r]], [[3n5s|3n5s]], [[3n5v|3n5v]], [[3n5w|3n5w]], [[3n5x|3n5x]], [[3n5y|3n5y]], [[3n5z|3n5z]], [[3n60|3n60]], [[3n61|3n61]], [[3n62|3n62]], [[3n63|3n63]], [[3n64|3n64]], [[3n65|3n65]], [[3n66|3n66]], [[3n67|3n67]], [[3n68|3n68]], [[3n69|3n69]], [[3n6a|3n6a]], [[3n6b|3n6b]], [[3n6c|3n6c]], [[3n6d|3n6d]], [[3n6e|3n6e]], [[3n6f|3n6f]], [[3n6g|3n6g]]</td></tr>
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<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=CAD:CACODYLIC+ACID'>CAD</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=XFJ:6,6-(PYRIDINE-3,5-DIYLDIETHANE-2,1-DIYL)BIS(4-METHYLPYRIDIN-2-AMINE)'>XFJ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<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=9913 Bos taurus])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3n5t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3n5t OCA], [https://pdbe.org/3n5t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3n5t RCSB], [https://www.ebi.ac.uk/pdbsum/3n5t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3n5t ProSAT]</span></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Nitric-oxide_synthase Nitric-oxide synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.39 1.14.13.39] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3n5t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3n5t OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3n5t RCSB], [http://www.ebi.ac.uk/pdbsum/3n5t PDBsum]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[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.
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In previous studies [Delker, S. L., et al. (2010), J. Am. Chem. Soc. 132, 5437-5442], we determined the crystal structures of neuronal nitric oxide synthase (nNOS) in complex with nNOS-selective chiral pyrrolidine inhibitors, designed to have an aminopyridine group bound over the heme where it can electrostatically interact with the conserved active site Glu residue. However, in addition to the expected binding mode with the (S,S)-cis inhibitors, an unexpected "flipped" orientation was observed for the (R,R)-cis enantiomers. In the flipped mode, the aminopyridine extends out of the active site where it interacts with one heme propionate. This prompted us to design and synthesize symmetric "double-headed" inhibitors with an aminopyridine at each end of a bridging ring structure [Xue, F., Delker, S. L., Li, H., Fang, J., Jamal, J., Martasek, P., Roman, L. J., Poulos, T. L., and Silverman, R. B. Symmetric double-headed aminopyridines, a novel strategy for potent and membrane-permeable inhibitors of neuronal nitric oxide synthase. J. Med. Chem. (submitted for publication)]. One aminopyridine should interact with the active site Glu and the other with the heme propionate. Crystal structures of these double-headed aminopyridine inhibitors in complexes with nNOS show unexpected and significant protein and heme conformational changes induced by inhibitor binding that result in removal of the tetrahydrobiopterin (H(4)B) cofactor and creation of a new Zn(2+) site. These changes are due to binding of a second inhibitor molecule that results in the displacement of H(4)B and the placement of the inhibitor pyridine group in position to serve as a Zn(2+) ligand together with Asp, His, and a chloride ion. Binding of the second inhibitor molecule and generation of the Zn(2+) site do not occur in eNOS. Structural requirements for creation of the new Zn(2+) site in nNOS were analyzed in detail. These observations open the way for the potential design of novel inhibitors selective for nNOS.
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Role of zinc in isoform-selective inhibitor binding to neuronal nitric oxide synthase .,Delker SL, Xue F, Li H, Jamal J, Silverman RB, Poulos TL Biochemistry. 2010 Dec 28;49(51):10803-10. Epub 2010 Dec 7. PMID:21138269<ref>PMID:21138269</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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==See Also==
==See Also==
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*[[Nitric Oxide Synthase|Nitric Oxide Synthase]]
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*[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Bos taurus]]
[[Category: Bos taurus]]
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[[Category: Nitric-oxide synthase]]
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[[Category: Large Structures]]
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[[Category: Delker, S L]]
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[[Category: Delker SL]]
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[[Category: Li, H]]
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[[Category: Li H]]
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[[Category: Poulos, T L]]
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[[Category: Poulos TL]]
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[[Category: Heme enzyme]]
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[[Category: Nitric oxide synthase]]
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[[Category: Oxidoreductase]]
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[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
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[[Category: Substrate inhibitor]]
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Current revision

Structure of endothelial nitric oxide synthase heme domain complexed with 6,6'-(2,2'-(pyridine-3,5-diyl)bis(ethane-2,1-diyl))bis(4-methylpyridin-2-amine)

PDB ID 3n5t

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