4ofz: Difference between revisions
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The | ==Structure of unliganded trehalose-6-phosphate phosphatase from Brugia malayi== | ||
<StructureSection load='4ofz' size='340' side='right'caption='[[4ofz]], [[Resolution|resolution]] 3.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4ofz]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Brugia_malayi Brugia malayi]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OFZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OFZ FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ofz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ofz OCA], [https://pdbe.org/4ofz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ofz RCSB], [https://www.ebi.ac.uk/pdbsum/4ofz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ofz ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:24992307</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4ofz" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Brugia malayi]] | |||
[[Category: Large Structures]] | |||
[[Category: Allen KN]] | |||
[[Category: Carlow CKS]] | |||
[[Category: Dunaway-Mariano D]] | |||
[[Category: Farelli JD]] | |||
