1RQJ

Active Conformation of Farnesyl Pyrophosphate Synthase Bound to Isopentyl Pyrophosphate and Risedronate


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.239 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.207 

wwPDB Validation   3D Report Full Report


This is version 1.5 of the entry. See complete history


Literature

Structural basis for bisphosphonate-mediated inhibition of isoprenoid biosynthesis

Hosfield, D.J.Zhang, Y.Dougan, D.R.Brooun, A.Tari, L.W.Swanson, R.V.Finn, J.

(2004) J Biol Chem 279: 8526-8529

  • DOI: https://doi.org/10.1074/jbc.C300511200
  • Primary Citation of Related Structures:  
    1RQI, 1RQJ, 1RTR

  • PubMed Abstract: 

    Farnesyl pyrophosphate synthetase (FPPS) synthesizes farnesyl pyrophosphate through successive condensations of isopentyl pyrophosphate with dimethylallyl pyrophosphate and geranyl pyrophosphate. Nitrogen-containing bisphosphonate drugs used to treat osteoclast-mediated bone resorption and tumor-induced hypercalcemia are potent inhibitors of the enzyme. Here we present crystal structures of substrate and bisphosphonate complexes of FPPS. The structures reveal how enzyme conformational changes organize conserved active site residues to exploit metal-induced ionization and substrate positioning for catalysis. The structures further demonstrate how nitrogen-containing bisphosphonates mimic a carbocation intermediate to inhibit the enzyme. Together, these FPPS complexes provide a structural template for the design of novel inhibitors that may prove useful for the treatment of osteoporosis and other clinical indications including cancer.


  • Organizational Affiliation

    Syrrx Inc., San Diego, California 92121, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Geranyltranstransferase
A, B
299Escherichia coliMutation(s): 0 
Gene Names: ISPAB0421
EC: 2.5.1.10
UniProt
Find proteins for P22939 (Escherichia coli (strain K12))
Explore P22939 
Go to UniProtKB:  P22939
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP22939
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
RIS
Query on RIS

Download Ideal Coordinates CCD File 
G [auth A],
L [auth B]
1-HYDROXY-2-(3-PYRIDINYL)ETHYLIDENE BIS-PHOSPHONIC ACID
C7 H11 N O7 P2
IIDJRNMFWXDHID-UHFFFAOYSA-N
IPE
Query on IPE

Download Ideal Coordinates CCD File 
F [auth A],
K [auth B]
3-METHYLBUT-3-ENYL TRIHYDROGEN DIPHOSPHATE
C5 H12 O7 P2
NUHSROFQTUXZQQ-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
C [auth A]
D [auth A]
E [auth A]
H [auth B]
I [auth B]
C [auth A],
D [auth A],
E [auth A],
H [auth B],
I [auth B],
J [auth B]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.239 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.207 
  • Space Group: P 41 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 88.8α = 90
b = 88.8β = 90
c = 174.988γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
SCALEPACKdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-03-02
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Derived calculations, Version format compliance
  • Version 1.3: 2013-05-22
    Changes: Non-polymer description
  • Version 1.4: 2017-10-04
    Changes: Advisory, Refinement description, Structure summary
  • Version 1.5: 2024-02-14
    Changes: Data collection, Database references, Derived calculations, Refinement description