PDBsum entry 5mym

Transcription

PDB id: 5mym

Contents

Protein chains

195 a.a.

205 a.a.

Ligands

HYV ×2

EDO ×4

Waters ×254

PDB id:

5mym

Name:

Transcription

Title:

Structure of transcriptional regulatory repressor protein - ethr from mycobacterium tuberculosis in complex with compound gsk2032710a at 2.28a resolution

Structure:

Hth-type transcriptional regulator ethr. Chain: a, b, c, d. Engineered: yes

Source:

Mycobacterium tuberculosis (strain atcc 25618 / h37rv). Organism_taxid: 83332. Strain: atcc 25618 / h37rv. Gene: ethr, etar, rv3855. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008

Resolution:

2.28Å R-factor: 0.178 R-free: 0.227

Authors:

V.Mendes,M.Blaszczyk,G.Mugumbate,T.L.Blundell

Key ref:

G.Mugumbate et al. (2017). Target Identification ofMycobacterium tuberculosisPhenotypic Hits Using a Concerted Chemogenomic, Biophysical, and Structural Approach. Front Pharmacol, 8, 681. PubMed id: 29018348

Date:

27-Jan-17 Release date: 25-Oct-17

Protein chains

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

Seq: 216 a.a.

Struc: 195 a.a.

Protein chains

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

Seq: 216 a.a.

Struc: 205 a.a.

Enzyme reactions

• Enzyme class: Chains A, B, C, D: E.C.?

Front Pharmacol 8:681 (2017)

PubMed id: 29018348

Target Identification ofMycobacterium tuberculosisPhenotypic Hits Using a Concerted Chemogenomic, Biophysical, and Structural Approach.

G.Mugumbate, V.Mendes, M.Blaszczyk, M.Sabbah, G.Papadatos, J.Lelievre, L.Ballell, D.Barros, C.Abell, T.L.Blundell, J.P.Overington.

ABSTRACT

Mycobacterium phenotypic hits are a good reservoir for new chemotypes for the treatment of tuberculosis. However, the absence of defined molecular targets and modes of action could lead to failure in drug development. Therefore, a combination of ligand-based and structure-based chemogenomic approaches followed by biophysical and biochemical validation have been used to identify targets forMycobacterium tuberculosisphenotypic hits. Our approach identified EthR and InhA as targets for several hits, with some showing dual activity against these proteins. From the 35 predicted EthR inhibitors, eight exhibited an IC₅₀below 50 μM againstM. tuberculosisEthR and three were confirmed to be also simultaneously active against InhA. Further hit validation was performed using X-ray crystallography yielding eight new crystal structures of EthR inhibitors. Although the EthR inhibitors attain their activity againstM. tuberculosisby hitting yet undefined targets, these results provide new lead compounds that could be further developed to be used to potentiate the effect of EthA activated pro-drugs, such as ethionamide, thus enhancing their bactericidal effect.