4NCR: Crystal Structure Of M. Tuberculosis Dpre1 In Complex With Pbtz169

Citation:
Abstract
The benzothiazinone lead compound, BTZ043, kills Mycobacterium tuberculosis by inhibiting the essential flavo-enzyme DprE1, decaprenylphosphoryl-beta-D-ribose 2-epimerase. Here, we synthesized a new series of piperazine-containing benzothiazinones (PBTZ) and show that, like BTZ043, the preclinical candidate PBTZ169 binds covalently to DprE1. The crystal structure of the DprE1-PBTZ169 complex reveals formation of a semimercaptal adduct with Cys387 in the active site and explains the irreversible inactivation of the enzyme. Compared to BTZ043, PBTZ169 has improved potency, safety and efficacy in zebrafish and mouse models of tuberculosis (TB). When combined with other TB drugs, PBTZ169 showed additive activity against M. tuberculosis in vitro except with bedaquiline (BDQ) where synergy was observed. A new regimen comprising PBTZ169, BDQ and pyrazinamide was found to be more efficacious than the standard three drug treatment in a murine model of chronic disease. PBTZ169 is thus an attractive drug candidate to treat TB in humans.
PDB ID: 4NCRDownload
MMDB ID: 117694
PDB Deposition Date: 2013/10/25
Updated in MMDB: 2014/04
Experimental Method:
x-ray diffraction
Resolution: 1.88  Å
Source Organism:
Similar Structures:
Biological Unit for 4NCR: monomeric; determined by software (PISA)
Molecular Components in 4NCR
Label Count Molecule
Protein (1 molecule)
1
Decaprenylphosphoryl-beta-d-ribose Oxidase
Molecule annotation
Chemicals (7 molecules)
1
1
2
1
3
4
4
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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