 |
PDBsum entry 4nbq
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Structural genomics for drug design against the pathogen coxiella burnetii.
|
|
|
Authors
|
|
M.C.Franklin,
J.Cheung,
M.J.Rudolph,
F.Burshteyn,
M.Cassidy,
E.Gary,
B.Hillerich,
Z.K.Yao,
P.R.Carlier,
M.Totrov,
J.D.Love.
|
|
|
Ref.
|
|
Proteins, 2015,
83,
2124-2136.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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. © 2015 Wiley Periodicals, Inc.
|
|
|
|
|
|
|
