4OFZ

Structure of unliganded trehalose-6-phosphate phosphatase from Brugia malayi


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.273 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.221 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Structure of the Trehalose-6-phosphate Phosphatase from Brugia malayi Reveals Key Design Principles for Anthelmintic Drugs.

Farelli, J.D.Galvin, B.D.Li, Z.Liu, C.Aono, M.Garland, M.Hallett, O.E.Causey, T.B.Ali-Reynolds, A.Saltzberg, D.J.Carlow, C.K.Dunaway-Mariano, D.Allen, K.N.

(2014) PLoS Pathog 10: e1004245-e1004245

  • DOI: https://doi.org/10.1371/journal.ppat.1004245
  • Primary Citation of Related Structures:  
    4OFZ

  • PubMed Abstract: 

    Parasitic nematodes are responsible for devastating illnesses that plague many of the world's poorest populations indigenous to the tropical areas of developing nations. Among these diseases is lymphatic filariasis, a major cause of permanent and long-term disability. Proteins essential to nematodes that do not have mammalian counterparts represent targets for therapeutic inhibitor discovery. One promising target is trehalose-6-phosphate phosphatase (T6PP) from Brugia malayi. In the model nematode Caenorhabditis elegans, T6PP is essential for survival due to the toxic effect(s) of the accumulation of trehalose 6-phosphate. T6PP has also been shown to be essential in Mycobacterium tuberculosis. We determined the X-ray crystal structure of T6PP from B. malayi. The protein structure revealed a stabilizing N-terminal MIT-like domain and a catalytic C-terminal C2B-type HAD phosphatase fold. Structure-guided mutagenesis, combined with kinetic analyses using a designed competitive inhibitor, trehalose 6-sulfate, identified five residues important for binding and catalysis. This structure-function analysis along with computational mapping provided the basis for the proposed model of the T6PP-trehalose 6-phosphate complex. The model indicates a substrate-binding mode wherein shape complementarity and van der Waals interactions drive recognition. The mode of binding is in sharp contrast to the homolog sucrose-6-phosphate phosphatase where extensive hydrogen-bond interactions are made to the substrate. Together these results suggest that high-affinity inhibitors will be bi-dentate, taking advantage of substrate-like binding to the phosphoryl-binding pocket while simultaneously utilizing non-native binding to the trehalose pocket. The conservation of the key residues that enforce the shape of the substrate pocket in T6PP enzymes suggest that development of broad-range anthelmintic and antibacterial therapeutics employing this platform may be possible.


  • Organizational Affiliation

    Department of Chemistry, Boston University, Boston, Massachusetts, United States of America.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Trehalose-phosphatase514Brugia malayiMutation(s): 0 
Gene Names: Bm1_08695
EC: 3.1.3.12
UniProt
Find proteins for A8NS89 (Brugia malayi)
Explore A8NS89 
Go to UniProtKB:  A8NS89
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA8NS89
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
MG
Query on MG

Download Ideal Coordinates CCD File 
B [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.273 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.221 
  • Space Group: P 64 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 166.94α = 90
b = 166.94β = 90
c = 99.562γ = 120
Software Package:
Software NamePurpose
HKL-3000data collection
MLPHAREphasing
PHENIXrefinement
HKL-3000data reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-07-16
    Type: Initial release
  • Version 1.1: 2018-01-24
    Changes: Structure summary