title: 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.
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.
authors: Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, United States.
authors: Aaron A
authors: AA
authors: Thompson
authors: Guan-Sheng
authors: GS
authors: Jiao
authors: Seongjin
authors: S
authors: Kim
authors: April
authors: A
authors: Thai
authors: Lynne
authors: L
authors: Cregar-Hernandez
authors: Stephen A
authors: SA
authors: Margosiak
authors: Alan T
authors: AT
authors: Johnson
authors: Gye Won
authors: GW
authors: Han
authors: Sean
authors: S
authors: O'Malley
authors: Raymond C
authors: RC
authors: Stevens
mesh_terms: D001665:Binding Sites; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry* / Q000378:metabolism; D003014:Clostridium botulinum / Q000201:enzymology*; D018360:Crystallography, X-Ray; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D015032:Zinc / Q000737:chemistry* / Q000378:metabolism
chemical_list: D002614:Chelating Agents; D006877:Hydroxamic Acids; D008024:Ligands; D009498:Neurotoxins; D045726:Metalloproteases; D019274:Botulinum Toxins, Type A; C545476:incobotulinumtoxinA; D015032:Zinc