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Structural genomics for drug design against the pathogen Coxiella burnetii
Author(s) -
Franklin Matthew C.,
Cheung Jonah,
Rudolph Michael J.,
Burshteyn Fiana,
Cassidy Michael,
Gary Ebony,
Hillerich Brandan,
Yao ZhongKe,
Carlier Paul R.,
Totrov Maxim,
Love James D.
Publication year - 2015
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.24841
Subject(s) - coxiella burnetii , in silico , dihydrofolate reductase , computational biology , biology , drug discovery , enzyme , biochemistry , microbiology and biotechnology , gene
Coxiella burnetii is a highly infectious bacterium and potential agent of bioterrorism. However, it has not been studied as extensively as other biological agents, and very few of its proteins have been structurally characterized. To address this situation, we undertook a study of critical metabolic enzymes in C. burnetii that have great potential as drug targets. We used high‐throughput techniques to produce novel crystal structures of 48 of these proteins. We selected one protein, C. burnetii dihydrofolate reductase (CbDHFR), for additional work to demonstrate the value of these structures for structure‐based drug design. This enzyme's structure reveals a feature in the substrate binding groove that is different between CbDHFR and human dihydrofolate reductase (hDHFR). We then identified a compound by in silico screening that exploits this binding groove difference, and demonstrated that this compound inhibits CbDHFR with at least 25‐fold greater potency than hDHFR. Since this binding groove feature is shared by many other prokaryotes, the compound identified could form the basis of a novel antibacterial agent effective against a broad spectrum of pathogenic bacteria. Proteins 2015; 83:2124–2136. © 2015 Wiley Periodicals, Inc.