5e0o

Brugia malayi Trehalose-6 Phosphate Phosphatase in complex with PEG at the active site.

spinqualitylabelsall models 5e0o, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5e0o is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: MG, PEG, SO4 Related: 4ofz Activity: Trehalose-phosphatase, with EC number 3.1.3.12 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [GOB1_BRUMA] Catalyzes the hydrolysis of trehalose 6-phosphate to trehalose and phosphate (By similarity). Publication Abstract from PubMed 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. Structure of the Trehalose-6-phosphate Phosphatase from Brugia malayi Reveals Key Design Principles for Anthelmintic Drugs.,Farelli JD, Galvin BD, Li Z, Liu C, Aono M, Garland M, Hallett OE, Causey TB, Ali-Reynolds A, Saltzberg DJ, Carlow CK, Dunaway-Mariano D, Allen KN PLoS Pathog. 2014 Jul 3;10(7):e1004245. doi: 10.1371/journal.ppat.1004245., eCollection 2014 Jul. PMID:24992307 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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