3NF3

Crystal structure of BoNT/A LC with JTH-NB-7239 peptide

Summary for 3NF3

• Entry DOI: 10.2210/pdb3nf3/pdb
• Related PRD ID: PRD_000997
• Descriptor: BoNT/A, JTH-NB72-39 inhibitor, ZINC ION, ... (5 entities in total)
• Functional Keywords: botulinum neurotoxin, snare, botulism, inhibition, metalloprotease, neurotransmission, neuromuscular junction, hydrolase, membrane, metal-binding, protease, secreted, toxin, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Clostridium botulinum
• Total number of polymer chains: 2
• Total formula weight: 49779.36

Authors

Zuniga, J.E. (deposition date: 2010-06-09, release date: 2010-07-21, Last modification date: 2023-11-22)

Primary citation

Zuniga, J.E.,Hammill, J.T.,Drory, O.,Nuss, J.E.,Burnett, J.C.,Gussio, R.,Wipf, P.,Bavari, S.,Brunger, A.T.
Iterative structure-based peptide-like inhibitor design against the botulinum neurotoxin serotype A.
Plos One, 5:e11378-e11378, 2010

PubMed Abstract: The botulinum neurotoxin serotype A light chain (BoNT/A LC) protease is the catalytic component responsible for the neuroparalysis that is characteristic of the disease state botulism. Three related peptide-like molecules (PLMs) were designed using previous information from co-crystal structures, synthesized, and assayed for in vitro inhibition against BoNT/A LC. Our results indicate these PLMS are competitive inhibitors of the BoNT/A LC protease and their K(i) values are in the nM-range. A co-crystal structure for one of these inhibitors was determined and reveals that the PLM, in accord with the goals of our design strategy, simultaneously involves both ionic interactions via its P1 residue and hydrophobic contacts by means of an aromatic group in the P2' position. The PLM adopts a helical conformation similar to previously determined co-crystal structures of PLMs, although there are also major differences to these other structures such as contacts with specific BoNT/A LC residues. Our structure further demonstrates the remarkable plasticity of the substrate binding cleft of the BoNT/A LC protease and provides a paradigm for iterative structure-based design and development of BoNT/A LC inhibitors.

PubMed: 20614028
DOI: 10.1371/journal.pone.0011378

Experimental method

X-RAY DIFFRACTION (2.4 Å)