3nlt

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<StructureSection load='3nlt' size='340' side='right'caption='[[3nlt]], [[Resolution|resolution]] 2.74&Aring;' scene=''>
<StructureSection load='3nlt' size='340' side='right'caption='[[3nlt]], [[Resolution|resolution]] 2.74&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3nlt]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bovin Bovin]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3NLT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NLT FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3nlt]] 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=3NLT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NLT FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3XF:6-({(3S,4S)-4-[2-({2,2-DIFLUORO-2-[(2R)-PIPERIDIN-2-YL]ETHYL}AMINO)ETHOXY]PYRROLIDIN-3-YL}METHYL)-4-METHYLPYRIDIN-2-AMINE'>3XF</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=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]] 2.74&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3nld|3nld]], [[3nle|3nle]], [[3nlf|3nlf]], [[3nlg|3nlg]], [[3nlh|3nlh]], [[3nli|3nli]], [[3nlj|3nlj]], [[3nlk|3nlk]], [[3nlm|3nlm]], [[3nln|3nln]], [[3nlo|3nlo]], [[3nlp|3nlp]], [[3nlq|3nlq]], [[3nlr|3nlr]], [[3nlu|3nlu]], [[3nlv|3nlv]], [[3nlw|3nlw]], [[3nlx|3nlx]], [[3nly|3nly]], [[3nlz|3nlz]], [[3nm0|3nm0]], [[3nny|3nny]], [[3nnz|3nnz]]</div></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=3XF:6-({(3S,4S)-4-[2-({2,2-DIFLUORO-2-[(2R)-PIPERIDIN-2-YL]ETHYL}AMINO)ETHOXY]PYRROLIDIN-3-YL}METHYL)-4-METHYLPYRIDIN-2-AMINE'>3XF</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=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 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9913 BOVIN])</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Nitric-oxide_synthase_(NADPH_dependent) Nitric-oxide synthase (NADPH dependent)], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=3nlt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nlt OCA], [https://pdbe.org/3nlt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3nlt RCSB], [https://www.ebi.ac.uk/pdbsum/3nlt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3nlt ProSAT]</span></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=3nlt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nlt OCA], [https://pdbe.org/3nlt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3nlt RCSB], [https://www.ebi.ac.uk/pdbsum/3nlt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3nlt ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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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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[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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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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In our efforts to discover neuronal isoform selective nitric oxide synthase (NOS) inhibitors, we have developed a series of compounds containing a pyrrolidine ring with two stereogenic centers. The enantiomerically pure compounds, (S,S) versus (R,R), exhibited two different binding orientations, with (R,R) inhibitors showing much better potency and selectivity. To improve the bioavailability of these inhibitors, we have introduced a CF(2) moiety geminal to an amino group in the long tail of one of these inhibitors, which reduced its basicity, resulting in compounds with monocationic character under physiological pH conditions. Biological evaluations have led to a nNOS inhibitor with a K(i) of 36 nM and high selectivity for nNOS over eNOS (3800-fold) and iNOS (1400-fold). MM-PBSA calculations indicated that the low pK(a) NH is, at least, partially protonated when bound to the active site. A comparison of rat oral bioavailability of the difluorinated compound to the parent molecule shows 22% for the difluorinated compound versus essentially no oral bioavailability for the parent compound. This indicates that the goal of this research to make compounds with only one protonated nitrogen atom at physiological pH to allow for membrane permeability, but which can become protonated when bound to NOS, has been accomplished.
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Potent, highly selective, and orally bioavailable gem-difluorinated monocationic inhibitors of neuronal nitric oxide synthase.,Xue F, Li H, Delker SL, Fang J, Martasek P, Roman LJ, Poulos TL, Silverman RB J Am Chem Soc. 2010 Oct 13;132(40):14229-38. PMID:20843082<ref>PMID:20843082</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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<div class="pdbe-citations 3nlt" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
*[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]]
*[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]]
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== References ==
 
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<references/>
 
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Bovin]]
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[[Category: Bos taurus]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Delker, S L]]
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[[Category: Delker SL]]
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[[Category: Fang, J]]
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[[Category: Fang J]]
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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: Silverman, R B]]
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[[Category: Silverman RB]]
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[[Category: Xue, F]]
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[[Category: Xue F]]
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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: Substrate inhibitor]]
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Current revision

Structure of endothelial nitric oxide synthase heme domain complexed with N1-{(3'S,4'S)-4'-[(6"-amino-4"-methylpyridin-2"-yl)methyl]pyrrolidin-3'-yl}- N2-(3'-fluorophenethyl)ethane-1,2-diamine tetrahydrochloride

PDB ID 3nlt

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