1YHL

Structure of the complex of Trypanosoma cruzi farnesyl diphosphate synthase with risedronate, dmapp and mg+2


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.177 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Structure and mechanism of the farnesyl diphosphate synthase from Trypanosoma cruzi: Implications for drug design.

Gabelli, S.B.McLellan, J.S.Montalvetti, A.Oldfield, E.Docampo, R.Amzel, L.M.

(2005) Proteins 62: 80-88

  • DOI: https://doi.org/10.1002/prot.20754
  • Primary Citation of Related Structures:  
    1YHK, 1YHL, 1YHM

  • PubMed Abstract: 

    Typanosoma cruzi, the causative agent of Chagas disease, has recently been shown to be sensitive to the action of the bisphosphonates currently used in bone resorption therapy. These compounds target the mevalonate pathway by inhibiting farnesyl diphosphate synthase (farnesyl pyrophosphate synthase, FPPS), the enzyme that condenses the diphosphates of C5 alcohols (isopentenyl and dimethylallyl) to form C10 and C15 diphosphates (geranyl and farnesyl). The structures of the T. cruzi FPPS (TcFPPS) alone and in two complexes with substrates and inhibitors reveal that following binding of the two substrates and three Mg2+ ions, the enzyme undergoes a conformational change consisting of a hinge-like closure of the binding site. In this conformation, it would be possible for the enzyme to bind a bisphosphonate inhibitor that spans the sites usually occupied by dimethylallyl diphosphate (DMAPP) and the homoallyl moiety of isopentenyl diphosphate. This observation may lead to the design of new, more potent anti-trypanosomal bisphosphonates, because existing FPPS inhibitors occupy only the DMAPP site. In addition, the structures provide an important mechanistic insight: after its formation, geranyl diphosphate can swing without leaving the enzyme, from the product site to the substrate site to participate in the synthesis of farnesyl diphosphate.


  • Organizational Affiliation

    Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
farnesyl pyrophosphate synthase362Trypanosoma cruziMutation(s): 0 
UniProt
Find proteins for Q8WS26 (Trypanosoma cruzi)
Explore Q8WS26 
Go to UniProtKB:  Q8WS26
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8WS26
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
RIS
Query on RIS

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

Download Ideal Coordinates CCD File 
F [auth A]DIMETHYLALLYL DIPHOSPHATE
C5 H12 O7 P2
CBIDRCWHNCKSTO-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
E [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
MG
Query on MG

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A],
D [auth A]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
RIS BindingDB:  1YHL IC50: 27 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.177 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.152α = 90
b = 58.152β = 90
c = 389.512γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
CCP4data scaling
AMoREphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2005-12-20
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Derived calculations, Version format compliance
  • Version 1.3: 2017-10-04
    Changes: Advisory, Structure summary
  • Version 1.4: 2024-02-14
    Changes: Data collection, Database references, Derived calculations