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| - | [[Image:3bgi.jpg|left|200px]] | |
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| - | <!--
| + | ==Thiopurine S-Methyltransferase== |
| - | The line below this paragraph, containing "STRUCTURE_3bgi", creates the "Structure Box" on the page.
| + | <StructureSection load='3bgi' size='340' side='right'caption='[[3bgi]], [[Resolution|resolution]] 1.80Å' scene=''> |
| - | You may change the PDB parameter (which sets the PDB file loaded into the applet)
| + | == Structural highlights == |
| - | or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
| + | <table><tr><td colspan='2'>[[3bgi]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BGI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3BGI FirstGlance]. <br> |
| - | or leave the SCENE parameter empty for the default display.
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</td></tr> |
| - | -->
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene></td></tr> |
| - | {{STRUCTURE_3bgi| PDB=3bgi | SCENE= }}
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3bgi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bgi OCA], [https://pdbe.org/3bgi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3bgi RCSB], [https://www.ebi.ac.uk/pdbsum/3bgi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3bgi ProSAT]</span></td></tr> |
| - | | + | </table> |
| - | '''Thiopurine S-Methyltransferase''' | + | == Function == |
| - | | + | [https://www.uniprot.org/uniprot/TPMT_MOUSE TPMT_MOUSE] Catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine. |
| - | | + | == Evolutionary Conservation == |
| - | ==Overview== | + | [[Image:Consurf_key_small.gif|200px|right]] |
| - | Thiopurine S-methyltransferase (TPMT) modulates the cytotoxic effects of thiopurine prodrugs such as 6-mercaptopurine by methylating them in a reaction using S-adenosyl- l-methionine as the donor. Patients with TPMT variant allozymes exhibit diminished levels of protein and/or enzyme activity and are at risk for thiopurine drug-induced toxicity. We have determined two crystal structures of murine TPMT, as a binary complex with the product S-adenosyl- l-homocysteine and as a ternary complex with S-adenosyl- l-homocysteine and the substrate 6-mercaptopurine, to 1.8 and 2.0 A resolution, respectively. Comparison of the structures reveals that an active site loop becomes ordered upon 6-mercaptopurine binding. The positions of the two ligands are consistent with the expected S N2 reaction mechanism. Arg147 and Arg221, the only polar amino acids near 6-mercaptopurine, are highlighted as possible participants in substrate deprotonation. To probe whether these residues are important for catalysis, point mutants were prepared in the human enzyme. Substitution of Arg152 (Arg147 in murine TPMT) with glutamic acid decreases V max and increases K m for 6-mercaptopurine but not K m for S-adenosyl- l-methionine. Substitution at this position with alanine or histidine and similar substitutions of Arg226 (Arg221 in murine TPMT) result in no effect on enzyme activity. The double mutant Arg152Ala/Arg226Ala exhibits a decreased V max and increased K m for 6-mercaptopurine. These observations suggest that either Arg152 or Arg226 may participate in some fashion in the TPMT reaction, with one residue compensating when the other is altered, and that Arg152 may interact with substrate more directly than Arg226, consistent with observations in the murine TPMT crystal structure.
| + | Check<jmol> |
| - | | + | <jmolCheckbox> |
| - | ==About this Structure== | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/bg/3bgi_consurf.spt"</scriptWhenChecked> |
| - | 3BGI is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BGI OCA].
| + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| - | | + | <text>to colour the structure by Evolutionary Conservation</text> |
| - | ==Reference== | + | </jmolCheckbox> |
| - | Structural basis of substrate recognition in thiopurine s-methyltransferase., Peng Y, Feng Q, Wilk D, Adjei AA, Salavaggione OE, Weinshilboum RM, Yee VC, Biochemistry. 2008 Jun 10;47(23):6216-25. Epub 2008 May 17. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18484748 18484748]
| + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3bgi ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | + | [[Category: Large Structures]] |
| | [[Category: Mus musculus]] | | [[Category: Mus musculus]] |
| - | [[Category: Single protein]]
| + | [[Category: Peng Y]] |
| - | [[Category: Thiopurine S-methyltransferase]]
| + | [[Category: Yee VC]] |
| - | [[Category: Peng, Y.]] | + | |
| - | [[Category: Yee, V C.]] | + | |
| - | [[Category: Cytoplasm]]
| + | |
| - | [[Category: Methyltransferase]]
| + | |
| - | [[Category: S-adenosyl-l-methionine]]
| + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jun 11 10:47:09 2008''
| + | |
