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| | <StructureSection load='5e0o' size='340' side='right'caption='[[5e0o]], [[Resolution|resolution]] 3.00Å' scene=''> | | <StructureSection load='5e0o' size='340' side='right'caption='[[5e0o]], [[Resolution|resolution]] 3.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5e0o]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5E0O OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5E0O FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5e0o]] 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=5E0O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5E0O FirstGlance]. <br> |
| - | </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>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ofz|4ofz]]</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>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Trehalose-phosphatase Trehalose-phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.12 3.1.3.12] </span></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=5e0o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5e0o OCA], [https://pdbe.org/5e0o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5e0o RCSB], [https://www.ebi.ac.uk/pdbsum/5e0o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5e0o ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5e0o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5e0o OCA], [http://pdbe.org/5e0o PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5e0o RCSB], [http://www.ebi.ac.uk/pdbsum/5e0o PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5e0o ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GOB1_BRUMA GOB1_BRUMA]] Catalyzes the hydrolysis of trehalose 6-phosphate to trehalose and phosphate (By similarity). | + | [https://www.uniprot.org/uniprot/GOB1_BRUMA GOB1_BRUMA] Catalyzes the hydrolysis of trehalose 6-phosphate to trehalose and phosphate (By similarity). |
| - | <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>
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| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 5e0o" style="background-color:#fffaf0;"></div>
| + | |
| - | == References ==
| + | |
| - | <references/>
| + | |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Brugia malayi]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Trehalose-phosphatase]]
| + | [[Category: Agarwal A]] |
| - | [[Category: Agarwal, A]] | + | [[Category: Misra-Bhattacharya S]] |
| - | [[Category: Misra-Bhattacharya, S]] | + | [[Category: Ravishankar R]] |
| - | [[Category: Ravishankar, R]] | + | |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Had]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Phosphatase]]
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