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Crystal structures of Klebsiella pneumoniae pantothenate kinase in complex with N‐substituted pantothenamides
Author(s) -
Li Buren,
Tempel Wolfram,
Smil David,
Bolshan Yuri,
Schapira Matthieu,
Park HeeWon
Publication year - 2013
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.24290
Subject(s) - klebsiella pneumoniae , microbiology and biotechnology , klebsiella , crystal (programming language) , biology , escherichia coli , biochemistry , gene , computer science , programming language
N‐Substituted pantothenamides are derivatives of pantothenate, the precursor in the biosynthesis of the essential metabolic cofactor coenzyme A (CoA). These compounds are substrates of pantothenate kinase (PanK) in the first step of CoA biosynthesis and possess antimicrobial activity against various pathogenic bacteria. Here we solved the crystal structure of the Klebsiella pneumoniae PanK (KpPanK) in complex with N‐pentylpantothenamide (N5‐Pan) to understand the molecular basis of its antimicrobial activity. The structure reveals a polar pocket interacting with the pantothenate moiety of N5‐Pan and an aromatic pocket loosely protecting the pentyl tail, suggesting that the introduction of an aromatic ring to a new pantothenamide may enhance the compound's affinity to KpPanK. To test this idea, we synthesized N‐pyridin‐3‐ylmethylpantothenamide (Np‐Pan) and solved its co‐crystal structure with KpPanK. The structure reveals two alternat conformations of the aromatic ring of Np‐Pan bound at the aromatic pocket, providing the basis for further improvement of pantothenamide binding to KpPanK. Proteins 2013; 81:1466–1472. © 2013 Wiley Periodicals, Inc.