2imc: Difference between revisions

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-[[Image:2imc.jpg|left|200px]]<br /><applet load="2imc" size="350" color="white" frame="true" align="right" spinBox="true"
-caption="2imc, resolution 2.00&Aring;" />
-'''Clostridium botulinum Neurotoxin Serotype A Light Chain, Residues 1-424'''<br />
-==Overview==
+==Clostridium botulinum Neurotoxin Serotype A Light Chain, Residues 1-424==
-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.
+<StructureSection load='2imc' size='340' side='right'caption='[[2imc]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2imc]] 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=2IMC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2IMC FirstGlance]. <br>
+</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>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=2imc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2imc OCA], [https://pdbe.org/2imc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2imc RCSB], [https://www.ebi.ac.uk/pdbsum/2imc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2imc ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/BXA1_CLOBH BXA1_CLOBH] Inhibits acetylcholine release. The botulinum toxin binds with high affinity to peripheral neuronal presynaptic membrane to the secretory vesicle protein SV2. It binds directly to the largest luminal loop of SV2A, SV2B and SV2C. It is then internalized by receptor-mediated endocytosis. The C-terminus of the heavy chain (H) is responsible for the adherence of the toxin to the cell surface while the N-terminus mediates transport of the light chain from the endocytic vesicle to the cytosol. After translocation, the light chain (L) hydrolyzes the 197-Gln-|-Arg-198 bond in SNAP-25, thereby blocking neurotransmitter release. Inhibition of acetylcholine release results in flaccid paralysis, with frequent heart or respiratory failure.
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/im/2imc_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</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=2imc ConSurf].
+<div style="clear:both"></div>
-==About this Structure==
+==See Also==
-IMC 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> as [http://en.wikipedia.org/wiki/ligand ligand]. 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=2IMC OCA].
+*[[Botulinum neurotoxin 3D structures|Botulinum neurotoxin 3D structures]]
+__TOC__
-==Reference==
+</StructureSection>
-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]
-[[Category: Bontoxilysin]]
 [[Category: Clostridium botulinum]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Allen, K.N.]]
+[[Category: Allen KN]]
-[[Category: Silvaggi, N.R.]]
+[[Category: Silvaggi NR]]
-[[Category: ZN]]
-[[Category: clostridium botulinum neurotoxin serotype a]]
-[[Category: protease inhibitors]]
-[[Category: substrate specificity]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 15:00:45 2008''