PDBsum entry 5nim

DNA binding protein

PDB id: 5nim

Contents

Protein chain

196 a.a.

Ligands

8YE

SO4

Waters ×148

PDB id:

5nim

Name:

DNA binding protein

Title:

Ethr complex

Structure:

Hth-type transcriptional regulator ethr. Chain: a. Engineered: yes

Source:

Mycobacterium tuberculosis. Organism_taxid: 1773. Gene: ethr, etar, rv3855. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.50Å R-factor: 0.177 R-free: 0.204

Authors:

E.Pohl,N.J.Tatum,J.C.Cole,A.R.Baulard

Key ref:

N.J.Tatum et al. (2017). New active leads for tuberculosis booster drugs by structure-based drug discovery. Org Biomol Chem, 15, 10245-10255. PubMed id: 29182187 DOI: 10.1039/c7ob00910k

Date:

24-Mar-17 Release date: 15-Nov-17

Protein chain

P9WMC1  (ETHR_MYCTU) -  HTH-type transcriptional regulator EthR from Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)

Seq: 216 a.a.

Struc: 196 a.a.

DOI no: 10.1039/c7ob00910k

Org Biomol Chem 15:10245-10255 (2017)

PubMed id: 29182187

New active leads for tuberculosis booster drugs by structure-based drug discovery.

N.J.Tatum, J.W.Liebeschuetz, J.C.Cole, R.Frita, A.Herledan, A.R.Baulard, N.Willand, E.Pohl.

ABSTRACT

The transcriptional repressor EthR from Mycobacterium tuberculosis, a member of the TetR family of prokaryotic homo-dimeric transcription factors, controls the expression of the mycobacterial mono-oxygenase EthA. EthA is responsible for the bio-activation of the second-line tuberculosis pro-drug ethionamide, and consequently EthR inhibitors boost drug efficacy. Here, we present a comprehensive in silico structure-based screening protocol that led to the identification of a number of novel scaffolds of EthR inhibitors in subsequent biophysical screening by thermal shift assay. Growth inhibition assays demonstrated that five of the twenty biophysical hits were capable of boosting ethionamide activity in vitro, with the best novel scaffold displaying an EC₅₀of 34 μM. In addition, the co-crystal structures of EthR with four new ligands at resolution ranging from 2.1 to 1.4 Å confirm the binding and inactivation mode, and will enable future lead development.