1m8e

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[[Image:1m8e.jpg|left|200px]]<br /><applet load="1m8e" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1m8e, resolution 2.90&Aring;" />
 
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'''inducible nitric oxide synthase with 7-nitroindazole bound'''<br />
 
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==Overview==
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==inducible nitric oxide synthase with 7-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='1m8e' size='340' side='right'caption='[[1m8e]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1m8e]] 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=1M8E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1M8E 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]] 2.9&#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=7NI:7-NITROINDAZOLE'>7NI</scene>, <scene name='pdbligand=H4B:5,6,7,8-TETRAHYDROBIOPTERIN'>H4B</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</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=1m8e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1m8e OCA], [https://pdbe.org/1m8e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1m8e RCSB], [https://www.ebi.ac.uk/pdbsum/1m8e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1m8e 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/m8/1m8e_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=1m8e 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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1M8E 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 <scene name='pdbligand=HEM:'>HEM</scene>, <scene name='pdbligand=H4B:'>H4B</scene> and <scene name='pdbligand=7NI:'>7NI</scene> 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://oca.weizmann.ac.il/oca-bin/ocashort?id=1M8E 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: 7NI]]
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[[Category: H4B]]
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[[Category: HEM]]
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[[Category: oxidoreductase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:52:37 2008''
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Current revision

inducible nitric oxide synthase with 7-nitroindazole bound

PDB ID 1m8e

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