4NCR

Crystal structure of M. tuberculosis DprE1 in complex with PBTZ169


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.88 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.190 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Towards a new combination therapy for tuberculosis with next generation benzothiazinones.

Makarov, V.Lechartier, B.Zhang, M.Neres, J.van der Sar, A.M.Raadsen, S.A.Hartkoorn, R.C.Ryabova, O.B.Vocat, A.Decosterd, L.A.Widmer, N.Buclin, T.Bitter, W.Andries, K.Pojer, F.Dyson, P.J.Cole, S.T.

(2014) EMBO Mol Med 6: 372-383

  • DOI: https://doi.org/10.1002/emmm.201303575
  • Primary Citation of Related Structures:  
    4NCR

  • PubMed 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.


  • Organizational Affiliation

    More Medicines for Tuberculosis (MM4TB) Consortium www.mm4tb.org.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
decaprenylphosphoryl-beta-D-ribose oxidase
A, B
481Mycobacterium tuberculosis H37RvMutation(s): 0 
Gene Names: dprE1MT3898Rv3790
EC: 1
UniProt
Find proteins for P9WJF1 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WJF1 
Go to UniProtKB:  P9WJF1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WJF1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FAD
Query on FAD

Download Ideal Coordinates CCD File 
D [auth A],
I [auth B]
FLAVIN-ADENINE DINUCLEOTIDE
C27 H33 N9 O15 P2
VWWQXMAJTJZDQX-UYBVJOGSSA-N
26J
Query on 26J

Download Ideal Coordinates CCD File 
C [auth A],
H [auth B]
2-(4-(cyclohexylmethyl)piperazin-1-yl)-8-nitro-6-(trifluoromethyl)-4H-benzo[e][1,3]thiazin-4-one, bound form
C20 H25 F3 N4 O2 S
XXSIMQFFRSHXQZ-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
G [auth A],
J [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
IMD
Query on IMD

Download Ideal Coordinates CCD File 
K [auth B]IMIDAZOLE
C3 H5 N2
RAXXELZNTBOGNW-UHFFFAOYSA-O
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.88 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.190 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 73.053α = 90
b = 84.999β = 101.1
c = 81.372γ = 90
Software Package:
Software NamePurpose
XDSdata scaling
PHASERphasing
REFMACrefinement
XDSdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-02-19
    Type: Initial release
  • Version 1.1: 2014-04-02
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description