2Z4V

S. cerevisiae geranylgeranyl pyrophosphate synthase in complex with magnesium and GGPP (inhibitory site)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.86 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.173 

Starting Model: experimental
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This is version 1.2 of the entry. See complete history


Literature

Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates: a crystallographic and computational investigation

Chen, C.K.-M.Hudock, M.P.Zhang, Y.Guo, R.-T.Cao, R.No, J.H.Liang, P.-H.Ko, T.-P.Chang, T.-H.Chang, S.-C.Song, Y.Axelson, J.Kumar, A.Wang, A.H.-J.Oldfield, E.

(2008) J Med Chem 51: 5594-5607

  • DOI: https://doi.org/10.1021/jm800325y
  • Primary Citation of Related Structures:  
    2Z4V, 2Z4W, 2Z4X, 2Z4Y, 2Z4Z, 2Z50, 2Z52, 2Z78, 2Z7I

  • PubMed Abstract: 

    We report the X-ray structures of several bisphosphonate inhibitors of geranylgeranyl diphosphate synthase, a target for anticancer drugs. Bisphosphonates containing unbranched side chains bind to either the farnesyl diphosphate (FPP) substrate site, the geranylgeranyl diphosphate (GGPP) product site, and in one case, both sites, with the bisphosphonate moiety interacting with 3 Mg (2+) that occupy the same position as found in FPP synthase. However, each of three "V-shaped" bisphosphonates bind to both the FPP and GGPP sites. Using the Glide program, we reproduced the binding modes of 10 bisphosphonates with an rms error of 1.3 A. Activities of the bisphosphonates in GGPPS inhibition were predicted with an overall error of 2x by using a comparative molecular similarity analysis based on a docked-structure alignment. These results show that some GGPPS inhibitors can occupy both substrate and product site and that binding modes as well as activity can be accurately predicted, facilitating the further development of GGPPS inhibitors as anticancer agents.


  • Organizational Affiliation

    Institute of Biochemical Sciences, National Taiwan University, Taipei 106, Taiwan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Geranylgeranyl pyrophosphate synthetase
A, B
340Saccharomyces cerevisiaeMutation(s): 0 
EC: 2.5.1.30 (PDB Primary Data), 2.5.1.1 (PDB Primary Data), 2.5.1.10 (PDB Primary Data), 2.5.1.29 (PDB Primary Data), 2.5.1 (UniProt)
UniProt
Find proteins for Q12051 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore Q12051 
Go to UniProtKB:  Q12051
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ12051
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.86 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.173 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 47.164α = 90
b = 115.944β = 90
c = 128.404γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-07-01
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description