Journal
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
Volume 81, Issue 8, Pages 1466-1472Publisher
WILEY-BLACKWELL
DOI: 10.1002/prot.24290
Keywords
pantothenate kinase; vitamin B-5 analogs; CoA synthesis inhibitors; enzyme-substrate analog complex; X-ray crystallography
Categories
Funding
- Defense Medical Research and Development Program FY10 Basic Research Award [DM102976]
- The Structural Genomics Consortium [1097737]
- Canadian Institutes for Health Research
- Canadian Foundation for Innovation
- Genome Canada through the Ontario Genomics Institute
- GlaxoSmithKline
- Karolinska Institutet
- Knut and Alice Wallenberg Foundation
- Ontario Innovation Trust
- Ontario Ministry for Research and Innovation
- Merck and Co., Inc.
- Novartis Research Foundation
- Swedish Agency for Innovation Systems
- Swedish Foundation for Strategic Research
- Wellcome Trust
- National Cancer Institute [Y1-CO-1020]
- National Institute of General Medical Sciences [Y1-GM-1104]
- UChicago Argonne
- LLC, for the United States Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]
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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. (c) 2013 Wiley Periodicals, Inc.
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