1vag

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(New page: 200px<br /><applet load="1vag" size="450" color="white" frame="true" align="right" spinBox="true" caption="1vag, resolution 2.0&Aring;" /> '''Neuronal nitric oxide...)
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[[Image:1vag.gif|left|200px]]<br /><applet load="1vag" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1vag, resolution 2.0&Aring;" />
 
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'''Neuronal nitric oxide synthase oxygenase domain complexed with the inhibitor AR-R17477'''<br />
 
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==Overview==
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==Neuronal nitric oxide synthase oxygenase domain complexed with the inhibitor AR-R17477==
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The high level of amino acid conservation and structural similarity of the, substrate-binding sites of the oxygenase domains of the nitric oxide, synthase (NOS) isoforms (eNOSoxy, iNOSoxy, nNOSoxy) make the, interpretation of the structural basis of inhibitor isoform specificity a, challenge, and provide few clues for the design of new selective, compounds. Crystal structures of iNOSoxy and nNOSoxy complexed with the, neuronal NOS-specific inhibitor AR-R17447 suggest that specificity is, provided by the interaction of the chlorophenyl group with an, isoform-unique substrate access channel residue (L337 in rat neuronal NOS, N115 in mouse inducible NOS). This is confirmed by biochemical analysis of, site-directed mutants. Inhibitors combining guanidinium-like structural, motifs with long chains specifically targeting this residue are good, candidates for rational isoform-specific drug design. Based on this, finding, modifications of AR-R17447 to improve the specificity for the, human isoforms are suggested.
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<StructureSection load='1vag' size='340' side='right'caption='[[1vag]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1vag]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1VAG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1VAG 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&#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=ARR:N-(4-{2-[(3-CHLOROBENZYL)AMINO]ETHYL}PHENYL)THIOPHENE-2-CARBOXIMIDAMIDE'>ARR</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1vag FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1vag OCA], [https://pdbe.org/1vag PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1vag RCSB], [https://www.ebi.ac.uk/pdbsum/1vag PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1vag ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/NOS1_RAT NOS1_RAT] Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum.
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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/va/1vag_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=1vag ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The high level of amino acid conservation and structural similarity of the substrate-binding sites of the oxygenase domains of the nitric oxide synthase (NOS) isoforms (eNOSoxy, iNOSoxy, nNOSoxy) make the interpretation of the structural basis of inhibitor isoform specificity a challenge, and provide few clues for the design of new selective compounds. Crystal structures of iNOSoxy and nNOSoxy complexed with the neuronal NOS-specific inhibitor AR-R17447 suggest that specificity is provided by the interaction of the chlorophenyl group with an isoform-unique substrate access channel residue (L337 in rat neuronal NOS, N115 in mouse inducible NOS). This is confirmed by biochemical analysis of site-directed mutants. Inhibitors combining guanidinium-like structural motifs with long chains specifically targeting this residue are good candidates for rational isoform-specific drug design. Based on this finding, modifications of AR-R17447 to improve the specificity for the human isoforms are suggested.
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==About this Structure==
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Structures of nitric oxide synthase isoforms complexed with the inhibitor AR-R17477 suggest a rational basis for specificity and inhibitor design.,Fedorov R, Vasan R, Ghosh DK, Schlichting I Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):5892-7. Epub 2004 Apr 7. PMID:15071192<ref>PMID:15071192</ref>
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1VAG is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with ZN, HEM, H4B and ARR 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=1VAG OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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Structures of nitric oxide synthase isoforms complexed with the inhibitor AR-R17477 suggest a rational basis for specificity and inhibitor design., Fedorov R, Vasan R, Ghosh DK, Schlichting I, Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):5892-7. Epub 2004 Apr 7. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15071192 15071192]
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</div>
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[[Category: Nitric-oxide synthase]]
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<div class="pdbe-citations 1vag" style="background-color:#fffaf0;"></div>
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[[Category: Rattus norvegicus]]
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[[Category: Single protein]]
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[[Category: Fedorov, R.]]
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[[Category: Ghosh, D.K.]]
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[[Category: Schlichting, I.]]
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[[Category: Vasan, R.]]
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[[Category: ARR]]
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[[Category: H4B]]
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[[Category: HEM]]
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[[Category: ZN]]
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[[Category: rat nnosoxy complex with ar-r17477]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 04:33:02 2007''
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==See Also==
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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__
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</StructureSection>
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[[Category: Large Structures]]
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[[Category: Rattus norvegicus]]
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[[Category: Fedorov R]]
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[[Category: Ghosh DK]]
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[[Category: Schlichting I]]
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[[Category: Vasan R]]

Current revision

Neuronal nitric oxide synthase oxygenase domain complexed with the inhibitor AR-R17477

PDB ID 1vag

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