PDBsum entry 5f0c

Transcription

PDB id

5f0c

Loading ...

Contents

			Protein chain

					193 a.a.

			Ligands

					5TE


					SO4 ×2

			Waters ×35

PDB id:

5f0c

Links

Name:

Transcription

Title:

Structure of transcriptional regulatory repressor protein - ethr from mycobacterium tuberculosis in complex with compound 4 at 1.87a resolution

Structure:

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

Source:

Mycobacterium tuberculosis cdc1551. Organism_taxid: 83331. Gene: ethr, etar, mt3970. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.87Å

R-factor:

0.198

R-free:

0.234

Authors:

S.Surade,M.Blaszczyk,P.O.Nikiforov,C.Abell,T.L.Blundell

Key ref:

P.O.Nikiforov et al. (2016). 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. PubMed id: 26806381 DOI: 10.1039/c5ob02630j

Date:

27-Nov-15

Release date:

03-Feb-16

PROCHECK

	Headers

	References

Protein chain

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

Seq: Struc:					216 a.a. 193 a.a.

Key:

PfamA domain

Secondary structure

CATH domain

DOI no: 10.1039/c5ob02630j	Org Biomol Chem 14:2318-2326 (2016)
PubMed id: 26806381

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

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.