1m8h

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(New page: 200px<br /><applet load="1m8h" size="450" color="white" frame="true" align="right" spinBox="true" caption="1m8h, resolution 2.85&Aring;" /> '''inducible nitric oxi...)
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[[Image:1m8h.gif|left|200px]]<br /><applet load="1m8h" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1m8h, resolution 2.85&Aring;" />
 
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'''inducible nitric oxide synthase with 6-nitroindazole bound'''<br />
 
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==Overview==
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==inducible nitric oxide synthase with 6-nitroindazole bound==
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Nitric oxide is a key signaling molecule in many biological processes, making regulation of nitric oxide levels highly desirable for human, medicine and for advancing our understanding of basic physiology., Designing inhibitors to specifically target one of the three nitric oxide, synthase (NOS) isozymes that form nitric oxide from the L-Arg substrate, poses a significant challenge due to the overwhelmingly conserved active, sites. We report here 10 new X-ray crystallographic structures of, inducible and endothelial NOS oxygenase domains cocrystallized with, chlorzoxazone and four nitroindazoles: 5-nitroindazole, 6-nitroindazole, 7-nitroindazole, and 3-bromo-7-nitroindazole. Each of these bicyclic, aromatic inhibitors has only one hydrogen bond donor and therefore cannot, form the bidentate hydrogen bonds that the L-Arg substrate makes with, Glu371. Instead, all of these inhibitors induce a conformational change in, Glu371, creating an active site with altered molecular recognition, properties. The cost of this conformational change is approximately 1-2, kcal, based on our measured constants for inhibitor binding to the, wild-type and E371A mutant proteins. These inhibitors derive affinity by, pi-stacking above the heme and replacing both intramolecular, (Glu371-Met368) and intermolecular (substrate-Trp366) hydrogen bonds to, the beta-sheet architecture underlying the active site. When bound to NOS, high-affinity inhibitors in this class are planar, whereas weaker, inhibitors are nonplanar. Isozyme differences were observed in the pterin, cofactor site, the heme propionate, and inhibitor positions. Computational, docking predictions match the crystallographic results, including the, Glu371 conformational change and inhibitor-binding orientations, and, support a combined crystallographic and computational approach to, isozyme-specific NOS inhibitor analysis and design.
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<StructureSection load='1m8h' size='340' side='right'caption='[[1m8h]], [[Resolution|resolution]] 2.85&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1m8h]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1M8H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1M8H FirstGlance]. <br>
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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]] 2.85&#8491;</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=6NI:6-NITROINDAZOLE'>6NI</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=SO4:SULFATE+ION'>SO4</scene></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=1m8h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1m8h OCA], [https://pdbe.org/1m8h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1m8h RCSB], [https://www.ebi.ac.uk/pdbsum/1m8h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1m8h ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/NOS2_MOUSE NOS2_MOUSE] Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In macrophages, NO mediates tumoricidal and bactericidal actions. Also has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such COX2.<ref>PMID:16373578</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/m8/1m8h_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1m8h ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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1M8H is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with SO4, HEM, H4B and 6NI as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1M8H OCA].
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*[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]]
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== References ==
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==Reference==
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<references/>
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Conformational changes in nitric oxide synthases induced by chlorzoxazone and nitroindazoles: crystallographic and computational analyses of inhibitor potency., Rosenfeld RJ, Garcin ED, Panda K, Andersson G, Aberg A, Wallace AV, Morris GM, Olson AJ, Stuehr DJ, Tainer JA, Getzoff ED, Biochemistry. 2002 Nov 26;41(47):13915-25. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12437348 12437348]
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__TOC__
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</StructureSection>
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[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Mus musculus]]
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[[Category: Nitric-oxide synthase]]
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[[Category: Aberg A]]
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[[Category: Single protein]]
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[[Category: Andersson G]]
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[[Category: Aberg, A.]]
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[[Category: Garcin ED]]
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[[Category: Andersson, G.]]
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[[Category: Getzoff ED]]
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[[Category: Garcin, E.D.]]
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[[Category: Panda K]]
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[[Category: Getzoff, E.D.]]
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[[Category: Rosenfeld RJ]]
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[[Category: Panda, K.]]
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[[Category: Stuehr DJ]]
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[[Category: Rosenfeld, R.J.]]
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[[Category: Tainer JA]]
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[[Category: Stuehr, D.J.]]
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[[Category: Wallace AV]]
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[[Category: Tainer, J.A.]]
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[[Category: Wallace, A.V.]]
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[[Category: 6NI]]
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[[Category: H4B]]
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[[Category: HEM]]
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[[Category: SO4]]
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[[Category: oxidoreductase]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 21:13:43 2007''
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Current revision

inducible nitric oxide synthase with 6-nitroindazole bound

PDB ID 1m8h

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