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Iterative structure-based peptide-like inhibitor design against the botulinum neurotoxin serotype A

Zuniga, JE and Hammill, JT and Drory, O and Nuss, JE and Burnett, JC and Gussio, R and Wipf, P and Bavari, S and Brunger, AT (2010) Iterative structure-based peptide-like inhibitor design against the botulinum neurotoxin serotype A. PLoS ONE, 5 (6).

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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 Ki 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. © 2010 Zuniga et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Zuniga, JE
Hammill, JT
Drory, O
Nuss, JE
Burnett, JC
Gussio, R
Wipf, Ppwipf@pitt.eduPWIPF
Bavari, S
Brunger, AT
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorAndreu, Antoni L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 12 August 2010
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 5
Number: 6
DOI or Unique Handle: 10.1371/journal.pone.0011378
Refereed: Yes
MeSH Headings: Botulinum Toxins, Type A--antagonists & inhibitors; Catalysis; Crystallization; Crystallography, X-Ray; Enzyme Inhibitors--chemistry; Enzyme Inhibitors--pharmacology; Models, Molecular; Peptides--chemistry; Peptides--pharmacology; Protein Conformation; Substrate Specificity
Other ID: NLM PMC2894858
PubMed Central ID: PMC2894858
PubMed ID: 20614028
Date Deposited: 03 Aug 2012 21:02
Last Modified: 02 Feb 2019 15:57
URI: http://d-scholarship.pitt.edu/id/eprint/13387

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