5JA0

Crystal structure of human FPPS with allosterically bound FPP


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.174 

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


Literature

Human farnesyl pyrophosphate synthase is allosterically inhibited by its own product.

Park, J.Zielinski, M.Magder, A.Tsantrizos, Y.S.Berghuis, A.M.

(2017) Nat Commun 8: 14132-14132

  • DOI: https://doi.org/10.1038/ncomms14132
  • Primary Citation of Related Structures:  
    5JA0

  • PubMed Abstract: 

    Farnesyl pyrophosphate synthase (FPPS) is an enzyme of the mevalonate pathway and a well-established therapeutic target. Recent research has focused around a newly identified druggable pocket near the enzyme's active site. Pharmacological exploitation of this pocket is deemed promising; however, its natural biological function, if any, is yet unknown. Here we report that the product of FPPS, farnesyl pyrophosphate (FPP), can bind to this pocket and lock the enzyme in an inactive state. The K d for this binding is 5-6 μM, within a catalytically relevant range. These results indicate that FPPS activity is sensitive to the product concentration. Kinetic analysis shows that the enzyme is inhibited through FPP accumulation. Having a specific physiological effector, FPPS is a bona fide allosteric enzyme. This allostery offers an exquisite mechanism for controlling prenyl pyrophosphate levels in vivo and thus contributes an additional layer of regulation to the mevalonate pathway.


  • Organizational Affiliation

    Department of Biochemistry, McGill University, 3649 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 0B1.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Farnesyl pyrophosphate synthaseA [auth F]375Homo sapiensMutation(s): 0 
Gene Names: FDPSFPSKIAA1293
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
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.174 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 110.89α = 90
b = 110.89β = 90
c = 77.48γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
REFMACphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-01-25
    Type: Initial release
  • Version 1.1: 2017-02-01
    Changes: Database references
  • Version 1.2: 2023-09-27
    Changes: Data collection, Database references, Refinement description