The 1.15A crystal structure of the Staphylococcus aureus methionyl-aminopeptidase and complexes with triazole based...

Area of Science:

• Biochemistry
• Structural Biology
• Microbiology

Background:

• Methionyl aminopeptidases (MetAPs) are crucial proteases removing N-terminal methionine from proteins.
• MetAPs are classified into type I and type II, with eukaryotes having both and prokaryotes possessing only type I.
• Inhibitors of MetAPs are of interest for antiangiogenic and antimicrobial applications.

Purpose of the Study:

• To determine the high-resolution crystal structure of Staphylococcus aureus MetAP-I.
• To investigate the binding of novel 1,2,4-triazole derivatives to MetAP-I.
• To characterize a new class of non-peptidic MetAP inhibitors.

Main Methods:

• X-ray crystallography was used to obtain the 1.15Å crystal structure of Staphylococcus aureus MetAP-I (apo-enzyme).
• Complex structures of MetAP-I with various 1,2,4-triazole derivatives were determined.
• Analysis of inhibitor binding within the enzyme's active site.

Main Results:

• The crystal structure revealed a typical "pita-bread" fold for Staphylococcus aureus MetAP-I.
• 1,2,4-triazole derivatives were observed to bind effectively in the active site.
• The N1 and N2 atoms of the triazole moiety complexed with two divalent ions in the active site.

Conclusions:

• 1,2,4-triazoles represent a novel class of potent, non-peptidic inhibitors for MetAP-I.
• The structural data provides a basis for the rational design of new antimicrobial agents targeting bacterial MetAPs.
• This study elucidates the mechanism of inhibition for this important class of enzymes.