4OFZ

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

Summary for 4OFZ

• Entry DOI: 10.2210/pdb4ofz/pdb
• Descriptor: Trehalose-phosphatase, MAGNESIUM ION (3 entities in total)
• Functional Keywords: had superfamily/rossmann fold, trehalose-6-phosphate phosphohydrolase, hydrolase
• Biological source: Brugia malayi (agent of lymphatic filariasis)
• Total number of polymer chains: 1
• Total formula weight: 57681.60

Authors

Farelli, J.D.,Allen, K.N.,Carlow, C.K.S.,Dunaway-Mariano, D. (deposition date: 2014-01-15, release date: 2014-07-16, Last modification date: 2024-11-20)

Primary citation

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.
Structure of the Trehalose-6-phosphate Phosphatase from Brugia malayi Reveals Key Design Principles for Anthelmintic Drugs.
Plos Pathog., 10:e1004245-e1004245, 2014

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.

PubMed: 24992307
DOI: 10.1371/journal.ppat.1004245

Experimental method

X-RAY DIFFRACTION (3 Å)