Structural genomics for drug design against the pathogen Coxiella burnetii

Matthew C. Franklin, Jonah Cheung, Michael J. Rudolph, Fiana Burshteyn, Michael Cassidy, Ebony Gary, Brandan Hillerich, Zhong Ke Yao, Paul R. Carlier, Maxim Totrov, James D. Love

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2124-2136
Number of pages13
JournalProteins: Structure, Function and Bioinformatics
Volume83
Issue number12
DOIs
StatePublished - Dec 1 2015
Externally publishedYes

Fingerprint

Coxiella burnetii
Tetrahydrofolate Dehydrogenase
Drug Design
Pathogens
Genomics
Pharmaceutical Preparations
Bacteria
Biological Warfare Agents
Biological Factors
Enzymes
Protein C
Computer Simulation
Screening
Proteins
Crystal structure
Throughput
Anti-Bacterial Agents
Substrates

Keywords

  • Antibiotic
  • Antifolate
  • Dihydrofolate reductase
  • Inhibitor
  • X-ray crystallography

ASJC Scopus subject areas

  • Biochemistry
  • Structural Biology
  • Molecular Biology

Cite this

Franklin, M. C., Cheung, J., Rudolph, M. J., Burshteyn, F., Cassidy, M., Gary, E., ... Love, J. D. (2015). Structural genomics for drug design against the pathogen Coxiella burnetii. Proteins: Structure, Function and Bioinformatics, 83(12), 2124-2136. https://doi.org/10.1002/prot.24841

Structural genomics for drug design against the pathogen Coxiella burnetii. / Franklin, Matthew C.; Cheung, Jonah; Rudolph, Michael J.; Burshteyn, Fiana; Cassidy, Michael; Gary, Ebony; Hillerich, Brandan; Yao, Zhong Ke; Carlier, Paul R.; Totrov, Maxim; Love, James D.

In: Proteins: Structure, Function and Bioinformatics, Vol. 83, No. 12, 01.12.2015, p. 2124-2136.

Research output: Contribution to journalArticle

Franklin, MC, Cheung, J, Rudolph, MJ, Burshteyn, F, Cassidy, M, Gary, E, Hillerich, B, Yao, ZK, Carlier, PR, Totrov, M & Love, JD 2015, 'Structural genomics for drug design against the pathogen Coxiella burnetii', Proteins: Structure, Function and Bioinformatics, vol. 83, no. 12, pp. 2124-2136. https://doi.org/10.1002/prot.24841
Franklin MC, Cheung J, Rudolph MJ, Burshteyn F, Cassidy M, Gary E et al. Structural genomics for drug design against the pathogen Coxiella burnetii. Proteins: Structure, Function and Bioinformatics. 2015 Dec 1;83(12):2124-2136. https://doi.org/10.1002/prot.24841
Franklin, Matthew C. ; Cheung, Jonah ; Rudolph, Michael J. ; Burshteyn, Fiana ; Cassidy, Michael ; Gary, Ebony ; Hillerich, Brandan ; Yao, Zhong Ke ; Carlier, Paul R. ; Totrov, Maxim ; Love, James D. / Structural genomics for drug design against the pathogen Coxiella burnetii. In: Proteins: Structure, Function and Bioinformatics. 2015 ; Vol. 83, No. 12. pp. 2124-2136.
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