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Serendipitous discovery of novel bacterial methionine aminopeptidase inhibitors
Author(s) -
Evdokimov Artem G.,
Pokross Matthew,
Walter Richard L.,
Mekel Marlene,
Barnett Bobby L.,
Amburgey Jack,
Seibel William L.,
Soper Shari J.,
Djung Jane F.,
Fairweather Neil,
Diven Conrad,
Rastogi Vinit,
Grinius Leo,
Klanke Charles,
Siehnel Richard,
Twinem Tracy,
Andrews Ryan,
Curnow Alan
Publication year - 2006
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.21207
Subject(s) - methionine , enzyme , aminopeptidase , biochemistry , drug discovery , cleave , computational biology , structural biology , chemistry , biology , amino acid , leucine
In this article we describe the application of structural biology methods to the discovery of novel potent inhibitors of methionine aminopeptidases. These enzymes are employed by the cells to cleave the N‐terminal methionine from nascent peptides and proteins. As this is one of the critical steps in protein maturation, it is very likely that inhibitors of these enzymes may prove useful as novel antibacterial agents. Involvement of crystallography at the very early stages of the inhibitor design process resulted in serendipitous discovery of a new inhibitor class, the pyrazole‐diamines. Atomic‐resolution structures of several inhibitors bound to the enzyme illuminate a new mode of inhibitor binding. Proteins 2007. © 2006 Wiley‐Liss, Inc.