2imc: Difference between revisions

Revision as of 18:53, 21 February 2008

Clostridium botulinum Neurotoxin Serotype A Light Chain, Residues 1-424

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

2IMC is a Single protein structure of sequence from Clostridium botulinum with as ligand. Active as Bontoxilysin, with EC number 3.4.24.69 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 Thu Feb 21 17:53:58 2008

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OCA

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 ==Overview==
-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.
+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 Structure==
@@ Line 10: / Line 10: @@
 ==Reference==
-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]
+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: Allen, K.N.]]
+[[Category: Allen, K N.]]
-[[Category: Silvaggi, N.R.]]
+[[Category: Silvaggi, N R.]]
 [[Category: ZN]]
 [[Category: clostridium botulinum neurotoxin serotype a]]
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 [[Category: substrate specificity]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 15:00:45 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:53:58 2008''