5F08

Structure of Transcriptional Regulatory Repressor Protein - EthR from Mycobacterium tuberculosis in complex with compound 14 at 1.92A resolution

Summary for 5F08

• Entry DOI: 10.2210/pdb5f08/pdb
• Descriptor: HTH-type transcriptional regulator EthR, ~{tert}-butyl ~{N}-methyl-~{N}-[[4-[4-(3-oxidanylidene-3-pyrrolidin-1-yl-propyl)piperidin-1-yl]phenyl]methyl]carbamate (3 entities in total)
• Functional Keywords: ethr, transcription, repressor, mycobacterium tuberculosis
• Biological source: Mycobacterium tuberculosis CDC1551
• Total number of polymer chains: 1
• Total formula weight: 25688.85

Authors

Surade, S.,Blaszczyk, M.,Nikiforov, P.O.,Abell, C.,Blundell, T.L. (deposition date: 2015-11-27, release date: 2016-02-03, Last modification date: 2024-01-10)

Primary citation

Nikiforov, P.O.,Surade, S.,Blaszczyk, M.,Delorme, V.,Brodin, P.,Baulard, A.R.,Blundell, T.L.,Abell, C.
A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters.
Org.Biomol.Chem., 14:2318-2326, 2016

PubMed Abstract: With the ever-increasing instances of resistance to frontline TB drugs there is the need to develop novel strategies to fight the worldwide TB epidemic. Boosting the effect of the existing second-line antibiotic ethionamide by inhibiting the mycobacterial transcriptional repressor protein EthR is an attractive therapeutic strategy. Herein we report the use of a fragment based drug discovery approach for the structure-guided systematic merging of two fragment molecules, each binding twice to the hydrophobic cavity of EthR from M. tuberculosis. These together fill the entire binding pocket of EthR. We elaborated these fragment hits and developed small molecule inhibitors which have a 100-fold improvement of potency in vitro over the initial fragments.

PubMed: 26806381
DOI: 10.1039/c5ob02630j

Experimental method

X-RAY DIFFRACTION (1.92 Å)