Research article summary (published 27 Sep 2009):

Crystallographic analysis of bacterial signal peptidase in ternary complex with arylomycin A2 and a beta-sultam inhibitor.

Full Abstract

Bacterial type I signal peptidase (SPase I), an essential membrane-bound endopeptidase with a unique Ser/Lys dyad mechanism, is being investigated as a potential novel antibiotic target. We present here binding and inhibition assays along with crystallographic data that shows that the lipohexapeptide-based natural product arylomycin A2 and the morpholino-beta-sultam derivative (BAL0019193) inhibit SPase I by binding to non-overlapping subsites near the catalytic center. The 2.0 A resolution crystal structure of the soluble catalytic domain of Escherichia coli SPase I (SPase I Delta2-75) in ternary complex with arylomycin A2 and BAL0019193 reveals the position of BAL0019193 adjacent to arylomycin A2 within the SPase I binding site. BAL0019193 binds in a noncovalent manner in close proximity to SPase I residues Ser88, Ser90, Lys145, Asn277, Ala279, and Glu307, as well as atom O45 of arylomycin A2. The binding mode of arylomycin A2 in this 2.0 A resolution ternary complex is compared to that seen in the previous 2.5 A resolution arylomycin A2-SPase cocrystal structure. This work contributes to our understanding of SPase I inhibitor/substrate recognition and should prove helpful in the further development of novel antibiotics based on the inhibition of SPase I.

Author information

Author/s: Luo, Chuanyun (C); Roussel, Patrick (P); Dreier, Jürg (J); Page, Malcolm G P (MG); Paetzel, Mark (M);

Affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, South Science Building 8888 University Drive, Burnaby, British Columbia, V5A 1S6 Canada.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Biochemistry (Biochemistry), published in United States. (Language: eng)

Reference: 2009-Sep; vol 48 (issue 38) : pp 8976-84

Dates: Created 2009/09/22; Completed 2009/10/09;

PMID: 19655811, status: MEDLINE (last retrieval date: 10/9/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Catalytic Domain Crystallography, X-Ray Escherichia coli Proteins - antagonists & inhibitors; chemistry Kinetics Macromolecular Substances Membrane Proteins - antagonists & inhibitors; chemistry Models, Molecular

Molecular Structure Oligopeptides - chemistry; pharmacology Peptide Fragments - antagonists & inhibitors; chemistry Serine Endopeptidases - chemistry Serine Proteinase Inhibitors - chemistry; pharmacology Static Electricity Sulfonamides - chemistry; pharmacology

Associated Chemicals: Escherichia coli Proteins (0) ; Macromolecular Substances (0) ; Membrane Proteins (0) ; Oligopeptides (0) ; Peptide Fragments (0) ; Serine Proteinase Inhibitors (0) ; Sulfonamides (0) ; arylomycin A2 (0) ; Serine Endopeptidases (EC 3.4.21.-) ; type I signal peptidase (EC 3.4.21.89)

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