Franklin_2015_Proteins_83_2124

Reference

Title : Structural genomics for drug design against the pathogen Coxiella burnetii - Franklin_2015_Proteins_83_2124
Author(s) : Franklin MC , Cheung J , Rudolph MJ , Burshteyn F , Cassidy M , Gary E , Hillerich B , Yao ZK , Carlier PR , Totrov M , Love JD
Ref : Proteins , 83 :2124 , 2015
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. Proteins 2015; 83:2124-2136. (c) 2015 Wiley Periodicals, Inc.

PubMedSearch : Franklin_2015_Proteins_83_2124
PubMedID: 26033498
Gene_locus related to this paper: coxbu-CBU1769

Related information

Gene_locus coxbu-CBU1769
Structure coxbu-CBU1769    3TRD

Citations formats

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 83 :2124

Franklin MC, Cheung J, Rudolph MJ, Burshteyn F, Cassidy M, Gary E, Hillerich B, Yao ZK, Carlier PR, Totrov M, Love JD (2015)
Proteins 83 :2124