3N1V

Human FPPS COMPLEX WITH FBS_01


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.18 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.220 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Allosteric non-bisphosphonate FPPS inhibitors identified by fragment-based discovery.

Jahnke, W.Rondeau, J.M.Cotesta, S.Marzinzik, A.Pelle, X.Geiser, M.Strauss, A.Gotte, M.Bitsch, F.Hemmig, R.Henry, C.Lehmann, S.Glickman, J.F.Roddy, T.P.Stout, S.J.Green, J.R.

(2010) Nat Chem Biol 6: 660-666

  • DOI: https://doi.org/10.1038/nchembio.421
  • Primary Citation of Related Structures:  
    3N1V, 3N1W, 3N3L, 3N45, 3N46, 3N49, 3N5H, 3N5J, 3N6K

  • PubMed Abstract: 

    Bisphosphonates are potent inhibitors of farnesyl pyrophosphate synthase (FPPS) and are highly efficacious in the treatment of bone diseases such as osteoporosis, Paget's disease and tumor-induced osteolysis. In addition, the potential for direct antitumor effects has been postulated on the basis of in vitro and in vivo studies and has recently been demonstrated clinically in early breast cancer patients treated with the potent bisphosphonate zoledronic acid. However, the high affinity of bisphosphonates for bone mineral seems suboptimal for the direct treatment of soft-tissue tumors. Here we report the discovery of the first potent non-bisphosphonate FPPS inhibitors. These new inhibitors bind to a previously unknown allosteric site on FPPS, which was identified by fragment-based approaches using NMR and X-ray crystallography. This allosteric and druggable pocket allows the development of a new generation of FPPS inhibitors that are optimized for direct antitumor effects in soft tissue.


  • Organizational Affiliation

    Center for Proteomic Chemistry and Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Basel, Switzerland. [email protected]


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
FARNESYL PYROPHOSPHATE SYNTHASEA [auth F]350Homo sapiensMutation(s): 0 
Gene Names: FDPSFPSKIAA1293
EC: 2.5.1.1 (PDB Primary Data), 2.5.1.10 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P14324 (Homo sapiens)
Explore P14324 
Go to UniProtKB:  P14324
PHAROS:  P14324
GTEx:  ENSG00000160752 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP14324
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
3N1 BindingDB:  3N1V IC50: min: 5.00e+5, max: 5.00e+8 (nM) from 2 assay(s)
PDBBind:  3N1V IC50: 5.00e+5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.18 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.220 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 111.372α = 90
b = 111.372β = 90
c = 77.512γ = 90
Software Package:
Software NamePurpose
XDSdata scaling
CNXrefinement
XDSdata reduction
XSCALEdata scaling
CNXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-08-18
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2024-02-21
    Changes: Data collection, Database references, Derived calculations