2imb: Difference between revisions

Revision as of 07:38, 4 May 2008

Clostridium botulinum Neurotoxin Serotype A Light Chain Inhibited by L-arginine hydroxamate

OverviewOverview

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.

About this StructureAbout this Structure

2IMB is a Single protein structure of sequence from Clostridium botulinum. Full crystallographic information is available from OCA.

ReferenceReference

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:17524984 Page seeded by OCA on Sun May 4 07:38:54 2008

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OCA

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 [[Image:2imb.jpg|left|200px]]
- {{Structure
+<!--
-|PDB= 2imb |SIZE=350|CAPTION= <scene name='initialview01'>2imb</scene>, resolution 2.41&Aring;
+The line below this paragraph, containing "STRUCTURE_2imb", creates the "Structure Box" on the page.
-|SITE=
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=AHL:N-HYDROXY-L-ARGININAMIDE'>AHL</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-|ACTIVITY= <span class='plainlinks'>[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] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE= botA, atx, bna ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1491 Clostridium botulinum])
+-->
-|DOMAIN=
+{{STRUCTURE_2imb|  PDB=2imb  |  SCENE=  }}
-|RELATEDENTRY=[[2ilp|2ILP]], [[2ima|2IMA]], [[2imc|2IMC]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2imb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2imb OCA], [http://www.ebi.ac.uk/pdbsum/2imb PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2imb RCSB]</span>
-}}
 '''Clostridium botulinum Neurotoxin Serotype A Light Chain Inhibited by L-arginine hydroxamate'''
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 [[Category: Allen, K N.]]
 [[Category: Silvaggi, N R.]]
-[[Category: clostridium botulinum neurotoxin serotype some]]
+[[Category: Clostridium botulinum neurotoxin serotype some]]
-[[Category: protease inhibitor]]
+[[Category: Protease inhibitor]]
-[[Category: substrate specificity]]
+[[Category: Substrate specificity]]
-[[Category: substrate switching]]
+[[Category: Substrate switching]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 07:38:54 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:46:02 2008''