2ima

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[[Image:2ima.jpg|left|200px]]<br /><applet load="2ima" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="2ima, resolution 1.94&Aring;" />
 
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'''Clostridium botulinum Neurotoxin Serotype A Light Chain Inhibited by 2,4-dichlorocinnamic hydroxamate'''<br />
 
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==Overview==
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==Clostridium botulinum Neurotoxin Serotype A Light Chain Inhibited by 2,4-dichlorocinnamic hydroxamate==
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The potential for the use of Clostridial neurotoxins as bioweapons makes, the development of small-molecule inhibitors of these deadly toxins a top, priority. Recently, screening of a random hydroxamate library identified a, small-molecule inhibitor of C. botulinum Neurotoxin Serotype A Light Chain, (BoNT/A-LC), 4-chlorocinnamic hydroxamate, a derivative of which has been, shown to have in vivo efficacy in mice and no toxicity. We describe the, X-ray crystal structures of BoNT/A-LC in complexes with two potent, small-molecule inhibitors. The structures of the enzyme with, 4-chlorocinnamic hydroxamate or 2,4-dichlorocinnamic hydroxamate bound are, compared to the structure of the enzyme complexed with L-arginine, hydroxamate, an inhibitor with modest affinity. Taken together, this suite, of structures provides surprising insights into the BoNT/A-LC active site, including unexpected conformational flexibility at the S1' site that, changes the electrostatic environment of the binding pocket. Information, gained from these structures will inform the design and optimization of, more effective small-molecule inhibitors of BoNT/A-LC.
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<StructureSection load='2ima' size='340' side='right'caption='[[2ima]], [[Resolution|resolution]] 1.94&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2ima]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Clostridium_botulinum Clostridium botulinum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IMA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2IMA 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]] 1.94&#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=GB4:(2E)-3-(2,4-DICHLOROPHENYL)-N-HYDROXYACRYLAMIDE'>GB4</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=2ima FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ima OCA], [https://pdbe.org/2ima PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ima RCSB], [https://www.ebi.ac.uk/pdbsum/2ima PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ima ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/Q84GJ4_CLOBO Q84GJ4_CLOBO]
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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/im/2ima_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=2ima 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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2IMA is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Clostridium_botulinum Clostridium botulinum] with <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=GB4:'>GB4</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Bontoxilysin Bontoxilysin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.69 3.4.24.69] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IMA OCA].
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*[[Botulinum neurotoxin 3D structures|Botulinum neurotoxin 3D structures]]
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__TOC__
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==Reference==
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</StructureSection>
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Structures of Clostridium botulinum Neurotoxin Serotype A Light Chain Complexed with Small-Molecule Inhibitors Highlight Active-Site Flexibility., Silvaggi NR, Boldt GE, Hixon MS, Kennedy JP, Tzipori S, Janda KD, Allen KN, Chem Biol. 2007 May;14(5):533-42. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17524984 17524984]
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[[Category: Bontoxilysin]]
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[[Category: Clostridium botulinum]]
[[Category: Clostridium botulinum]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Allen, K.N.]]
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[[Category: Allen KN]]
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[[Category: Silvaggi, N.R.]]
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[[Category: Silvaggi NR]]
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[[Category: GB4]]
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[[Category: ZN]]
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[[Category: clostridium botulinum neurotoxin serotype a]]
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[[Category: protease inhibitors]]
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[[Category: substrate specificity]]
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[[Category: substrate switching]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 15:00:43 2008''
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Current revision

Clostridium botulinum Neurotoxin Serotype A Light Chain Inhibited by 2,4-dichlorocinnamic hydroxamate

PDB ID 2ima

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