4HEV

Clostridium Botulinum Serotype A Light Chain Inhibited By Adamantane Hydroxamate

Summary for 4HEV

• Entry DOI: 10.2210/pdb4hev/pdb
• Descriptor: Botulinum neurotoxin type A light chain, ZINC ION, N-hydroxy-2-[(3S,5S,7S)-tricyclo[3.3.1.1~3,7~]dec-1-yl]acetamide, ... (4 entities in total)
• Functional Keywords: zn2+-dependent metalloprotease, 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: P10845
• Total number of polymer chains: 2
• Total formula weight: 101753.48

Authors

Silvaggi, N.R.,Allen, K.N. (deposition date: 2012-10-04, release date: 2013-01-23, Last modification date: 2023-09-20)

Primary citation

Silhar, P.,Silvaggi, N.R.,Pellett, S.,Johnson, E.A.,Allen, K.N.,Janda, K.D.
Evaluation of adamantane hydroxamates as botulinum neurotoxin inhibitors: synthesis, crystallography, modeling, kinetic and cellular based studies.
Bioorg.Med.Chem., 21:1344-1348, 2013

PubMed Abstract: Botulinum neurotoxins (BoNTs) are the most lethal biotoxins known to mankind and are responsible for the neuroparalytic disease botulism. Current treatments for botulinum poisoning are all protein based and thus have a limited window of treatment opportunity. Inhibition of the BoNT light chain protease (LC) has emerged as a therapeutic strategy for the treatment of botulism as it may provide an effective post exposure remedy. Using a combination of crystallographic and modeling studies a series of hydroxamates derived from 1-adamantylacetohydroxamic acid (3a) were prepared. From this group of compounds, an improved potency of about 17-fold was observed for two derivatives. Detailed mechanistic studies on these structures revealed a competitive inhibition model, with a K(i)=27 nM, which makes these compounds some of the most potent small molecule, non-peptidic BoNT/A LC inhibitors reported to date.

PubMed: 23340139
DOI: 10.1016/j.bmc.2012.12.001

Experimental method

X-RAY DIFFRACTION (2.5 Å)