4ONC

Crystal Structure of Mycobacterium Tuberculosis Decaprenyl Diphosphate Synthase in Complex with BPH-640

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.83 Å
  • R-Value Free: 0.198 
  • R-Value Work: 0.157 
  • R-Value Observed: 0.159 

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Literature

Structure and Inhibition of Tuberculosinol Synthase and Decaprenyl Diphosphate Synthase from Mycobacterium tuberculosis

Chan, H.C., Feng, X., Ko, T.P., Huang, C.H., Hu, Y., Zheng, Y., Bogue, S., Nakano, C., Hoshino, T., Zhang, L., Lv, P., Liu, W., Crick, D.C., Liang, P.H., Wang, A.H., Oldfield, E., Guo, R.T.

(2014) J Am Chem Soc 136: 2892-2896

  • DOI: https://doi.org/10.1021/ja413127v
  • Primary Citation of Related Structures:  
    3WQK, 3WQL, 3WQM, 3WQN, 4KT8, 4ONC

  • PubMed Abstract: 

    We have obtained the structure of the bacterial diterpene synthase, tuberculosinol/iso-tuberculosinol synthase (Rv3378c) from Mycobacterium tuberculosis , a target for anti-infective therapies that block virulence factor formation. This phosphatase adopts the same fold as found in the Z- or cis-prenyltransferases. We also obtained structures containing the tuberculosinyl diphosphate substrate together with one bisphosphonate inhibitor-bound structure. These structures together with the results of site-directed mutagenesis suggest an unusual mechanism of action involving two Tyr residues. Given the similarity in local and global structure between Rv3378c and the M. tuberculosis cis-decaprenyl diphosphate synthase (DPPS; Rv2361c), the possibility exists for the development of inhibitors that target not only virulence but also cell wall biosynthesis, based in part on the structures reported here.

    • Organizational Affiliation: 

    Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology , Tianjin 300308, China.


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Decaprenyl diphosphate synthase
A, B
284Mycobacterium tuberculosisMutation(s): 0 
Gene Names: Rv2361c
EC: 2.5.1.86 (PDB Primary Data), 2.5.1.87 (PDB Primary Data)
UniProt
Find proteins for P9WFF7 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WFF7 
Go to UniProtKB:  P9WFF7
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WFF7
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
40B
Query on 40B
Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]		[hydroxy(1,1':3',1''-terphenyl-3-yl)methanediyl]bis(phosphonic acid)
C19 H18 O7 P2
QLUPVXJJKKYIHH-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
40B Binding MOAD:  4ONC Kd: 410 (nM) from 1 assay(s)
BindingDB:  4ONC IC50: min: 410, max: 610 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.83 Å
  • R-Value Free: 0.198 
  • R-Value Work: 0.157 
  • R-Value Observed: 0.159 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.809α = 90
b = 89.167β = 90
c = 93.88γ = 90
Software Package:
Software NamePurpose
CCP4model building
REFMACrefinement
HKL-3000data reduction
HKL-3000data scaling
CCP4phasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-04-02
    Type: Initial release
  • Version 1.1: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description