4KW5

M. tuberculosis DprE1 in complex with inhibitor TCA1

Summary for 4KW5

• Entry DOI: 10.2210/pdb4kw5/pdb
• Related: 4FDN 4FDO 4FDP 4FEH 4FF6
• Descriptor: Oxidoreductase, FLAVIN-ADENINE DINUCLEOTIDE, ethyl ({2-[(1,3-benzothiazol-2-ylcarbonyl)amino]thiophen-3-yl}carbonyl)carbamate, ... (6 entities in total)
• Functional Keywords: alpha/beta fold, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 103107.27

Authors

Batt, S.M.,Besra, G.S.,Futterer, K. (deposition date: 2013-05-23, release date: 2013-07-10, Last modification date: 2023-09-20)

Primary citation

Wang, F.,Sambandan, D.,Halder, R.,Wang, J.,Batt, S.M.,Weinrick, B.,Ahmad, I.,Yang, P.,Zhang, Y.,Kim, J.,Hassani, M.,Huszar, S.,Trefzer, C.,Ma, Z.,Kaneko, T.,Mdluli, K.E.,Franzblau, S.,Chatterjee, A.K.,Johnson, K.,Mikusova, K.,Besra, G.S.,Futterer, K.,Jacobs, W.R.,Schultz, P.G.
Identification of a small molecule with activity against drug-resistant and persistent tuberculosis.
Proc.Natl.Acad.Sci.USA, 110:E2510-E2517, 2013

PubMed Abstract: A cell-based phenotypic screen for inhibitors of biofilm formation in mycobacteria identified the small molecule TCA1, which has bactericidal activity against both drug-susceptible and -resistant Mycobacterium tuberculosis (Mtb) and sterilizes Mtb in vitro combined with rifampicin or isoniazid. In addition, TCA1 has bactericidal activity against nonreplicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models both alone and combined with rifampicin or isoniazid. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb persistence. Genetic and affinity-based methods identified decaprenyl-phosphoryl-β-D-ribofuranose oxidoreductase DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as targets responsible for the activity of TCA1. These in vitro and in vivo results indicate that this compound functions by a unique mechanism and suggest that TCA1 may lead to the development of a class of antituberculosis agents.

PubMed: 23776209
DOI: 10.1073/pnas.1309171110

Experimental method

X-RAY DIFFRACTION (2.612 Å)