3UJ6

SeMet Phosphoethanolamine methyltransferase from Plasmodium falciparum in complex with SAM and PO4


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.97 Å
  • R-Value Free: 0.185 
  • R-Value Work: 0.149 
  • R-Value Observed: 0.153 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure and reaction mechanism of phosphoethanolamine methyltransferase from the malaria parasite Plasmodium falciparum: an antiparasitic drug target.

Lee, S.G.Kim, Y.Alpert, T.D.Nagata, A.Jez, J.M.

(2012) J Biol Chem 287: 1426-1434

  • DOI: https://doi.org/10.1074/jbc.M111.315267
  • Primary Citation of Related Structures:  
    3UJ6, 3UJ7, 3UJ8, 3UJ9, 3UJA, 3UJB, 3UJC, 3UJD

  • PubMed Abstract: 

    In the malarial parasite Plasmodium falciparum, a multifunctional phosphoethanolamine methyltransferase (PfPMT) catalyzes the methylation of phosphoethanolamine (pEA) to phosphocholine for membrane biogenesis. This pathway is also found in plant and nematodes, but PMT from these organisms use multiple methyltransferase domains for the S-adenosylmethionine (AdoMet) reactions. Because PfPMT is essential for normal growth and survival of Plasmodium and is not found in humans, it is an antiparasitic target. Here we describe the 1.55 Å resolution crystal structure of PfPMT in complex with AdoMet by single-wavelength anomalous dispersion phasing. In addition, 1.19-1.52 Å resolution structures of PfPMT with pEA (substrate), phosphocholine (product), sinefungin (inhibitor), and both pEA and S-adenosylhomocysteine bound were determined. These structures suggest that domain rearrangements occur upon ligand binding and provide insight on active site architecture defining the AdoMet and phosphobase binding sites. Functional characterization of 27 site-directed mutants identifies critical active site residues and suggests that Tyr-19 and His-132 form a catalytic dyad. Kinetic analysis, isothermal titration calorimetry, and protein crystallography of the Y19F and H132A mutants suggest a reaction mechanism for the PMT. Not only are Tyr-19 and His-132 required for phosphobase methylation, but they also form a "catalytic" latch that locks ligands in the active site and orders the site for catalysis. This study provides the first insight on this antiparasitic target enzyme essential for survival of the malaria parasite; however, further studies of the multidomain PMT from plants and nematodes are needed to understand the evolutionary division of metabolic function in the phosphobase pathway of these organisms.


  • Organizational Affiliation

    Department of Biology, Washington University, St. Louis, Missouri 63130, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Phosphoethanolamine N-methyltransferase266Plasmodium falciparumMutation(s): 0 
Gene Names: PMT
UniProt
Find proteins for Q8IDQ9 (Plasmodium falciparum (isolate 3D7))
Explore Q8IDQ9 
Go to UniProtKB:  Q8IDQ9
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8IDQ9
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
SAM
Query on SAM

Download Ideal Coordinates CCD File 
B [auth A]S-ADENOSYLMETHIONINE
C15 H22 N6 O5 S
MEFKEPWMEQBLKI-FCKMPRQPSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
C [auth A]PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
MSE
Query on MSE
A
L-PEPTIDE LINKINGC5 H11 N O2 SeMET
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.97 Å
  • R-Value Free: 0.185 
  • R-Value Work: 0.149 
  • R-Value Observed: 0.153 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 89.388α = 90
b = 44.151β = 108.61
c = 77.064γ = 90
Software Package:
Software NamePurpose
HKL-3000data collection
SHELXSphasing
PHENIXrefinement
HKL-3000data reduction
HKL-3000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-11-30
    Type: Initial release
  • Version 1.1: 2011-12-07
    Changes: Atomic model, Other
  • Version 1.2: 2012-03-21
    Changes: Database references