6N82

Crystal structure of human FPPS in complex with an allosteric inhibitor YF-02037

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.174 

Starting Model: experimental
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Literature

Chirality-Driven Mode of Binding of alpha-Aminophosphonic Acid-Based Allosteric Inhibitors of the Human Farnesyl Pyrophosphate Synthase (hFPPS).

Feng, Y., Park, J., Li, S.G., Boutin, R., Viereck, P., Schilling, M.A., Berghuis, A.M., Tsantrizos, Y.S.

(2019) J Med Chem 62: 9691-9702

  • DOI: https://doi.org/10.1021/acs.jmedchem.9b01104
  • Primary Citation of Related Structures:  
    6N7Y, 6N7Z, 6N82, 6N83, 6OAG, 6OAH

  • PubMed Abstract: 

    Thienopyrimidine-based allosteric inhibitors of the human farnesyl pyrophosphate synthase (hFPPS), characterized by a chiral α-aminophosphonic acid moiety, were synthesized as enantiomerically enriched pairs, and their binding mode was investigated by X-ray crystallography. A general consensus in the binding orientation of all ( R )- and ( S )-enantiomers was revealed. This finding is a prerequisite for establishing a reliable structure-activity relationship (SAR) model.

    • Organizational Affiliation: 

    Department of Chemistry , McGill University , 801 Sherbrooke Street West , Montreal , Quebec H3A 0B8 , Canada.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Farnesyl pyrophosphate synthaseA [auth F]375Homo sapiensMutation(s): 0 
Gene Names: FDPS, FPS, KIAA1293
EC: 2.5.1.10 (PDB Primary Data), 2.5.1.1 (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
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  • Reference Sequence
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
YF7
Query on YF7
Download Ideal Coordinates CCD File 
C [auth F],
D [auth F]		[(1S)-1-{[6-(3-chloro-4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]amino}-2-(3-fluorophenyl)ethyl]phosphonic acid
C21 H18 Cl F N3 O3 P S
ZSPBSSJYWQDARC-IBGZPJMESA-N
PGE
Query on PGE
Download Ideal Coordinates CCD File 
E [auth F]TRIETHYLENE GLYCOL
C6 H14 O4
ZIBGPFATKBEMQZ-UHFFFAOYSA-N
PO4
Query on PO4
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I [auth F]PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
GOL
Query on GOL
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B [auth F]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
EDO
Query on EDO
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F
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
CL
Query on CL
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G [auth F],
H [auth F]		CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
YF7 BindingDB:  6N82 IC50: 860 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.174 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 110.92α = 90
b = 110.92β = 90
c = 77.53γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
REFMACphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-11-06
    Type: Initial release
  • Version 1.1: 2019-11-27
    Changes: Database references
  • Version 1.2: 2023-10-11
    Changes: Data collection, Database references, Refinement description