3QIZ

Crystal Structure of BoNT/A LC complexed with Hydroxamate-based Inhibitor PT-2

Summary for 3QIZ

• Entry DOI: 10.2210/pdb3qiz/pdb
• Related: 3QIX 3QIY 3QJ0
• Descriptor: Botulinum neurotoxin type A, ZINC ION, (2S,4R)-2-(2-{[3-(4-fluoro-3-methylphenyl)propyl](methyl)amino}ethyl)-4-(4-fluorophenyl)-N-hydroxy-4-methoxybutanamide, ... (5 entities in total)
• Functional Keywords: botulinum, bont, neurotoxin, toxin, hydroxamate, inhibitor, metalloprotease, protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Clostridium botulinum
• Cellular location: Botulinum neurotoxin A light chain: Secreted. Botulinum neurotoxin A heavy chain: Secreted: A5HZZ9
• Total number of polymer chains: 1
• Total formula weight: 49981.71

Authors

Thompson, A.A.,Han, G.W.,Stevens, R.C. (deposition date: 2011-01-28, release date: 2011-04-13, Last modification date: 2023-09-13)

Primary citation

Thompson, A.A.,Jiao, G.S.,Kim, S.,Thai, A.,Cregar-Hernandez, L.,Margosiak, S.A.,Johnson, A.T.,Han, G.W.,O'Malley, S.,Stevens, R.C.
Structural Characterization of Three Novel Hydroxamate-Based Zinc Chelating Inhibitors of the Clostridium botulinum Serotype A Neurotoxin Light Chain Metalloprotease Reveals a Compact Binding Site Resulting from 60/70 Loop Flexibility.
Biochemistry, 50:4019-4028, 2011

PubMed Abstract: Neurotoxins synthesized by Clostridium botulinum bacteria (BoNT), the etiological agent of human botulism, are extremely toxic proteins making them high-risk agents for bioterrorism. Small molecule inhibitor development has been focused on the light chain zinc-dependent metalloprotease domain of the neurotoxin, an effort that has been hampered by its relatively flexible active site. Developed in concert with structure--activity relationship studies, the X-ray crystal structures of the complex of BoNT serotype A light chain (BoNT/A LC) with three different micromolar-potency hydroxamate-based inhibitors are reported here. Comparison with an unliganded BoNT/A LC structure reveals significant changes in the active site as a result of binding by the unique inhibitor scaffolds. The 60/70 loop at the opening of the active site pocket undergoes the largest conformational change, presumably through an induced-fit mechanism, resulting in the most compact catalytic pocket observed in all known BoNT/A LC structures.

PubMed: 21434688
DOI: 10.1021/bi2001483

Experimental method

X-RAY DIFFRACTION (2 Å)