6ky6

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==Crystal struture of a thermostable aldo-keto reductase Tm1743 in complexs with inhibitor epalrestat in space group P3221==
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==Crystal structure of a thermostable aldo-keto reductase Tm1743 in complexs with inhibitor epalrestat in space group P3221cc==
<StructureSection load='6ky6' size='340' side='right'caption='[[6ky6]], [[Resolution|resolution]] 2.07&Aring;' scene=''>
<StructureSection load='6ky6' size='340' side='right'caption='[[6ky6]], [[Resolution|resolution]] 2.07&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6ky6]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KY6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6KY6 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6ky6]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Thermotoga_maritima_MSB8 Thermotoga maritima MSB8]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KY6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6KY6 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EPR:{5-[(2E)-2-METHYL-3-PHENYLPROP-2-EN-1-YLIDENE]-4-OXO-2-THIOXO-1,3-THIAZOLIDIN-3-YL}ACETIC+ACID'>EPR</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.07&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6kiy|6kiy]], [[6kik|6kik]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EPR:{5-[(2E)-2-METHYL-3-PHENYLPROP-2-EN-1-YLIDENE]-4-OXO-2-THIOXO-1,3-THIAZOLIDIN-3-YL}ACETIC+ACID'>EPR</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ky6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ky6 OCA], [http://pdbe.org/6ky6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ky6 RCSB], [http://www.ebi.ac.uk/pdbsum/6ky6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ky6 ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6ky6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ky6 OCA], [https://pdbe.org/6ky6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ky6 RCSB], [https://www.ebi.ac.uk/pdbsum/6ky6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ky6 ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
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[https://www.uniprot.org/uniprot/Q9X265_THEMA Q9X265_THEMA]
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Tolrestat and epalrestat have been characterized as noncompetitive inhibitors of aldo-ketone reductase 1B1 (AKR1B1), a leading drug target for the treatment of type 2 diabetes complications. However, clinical applications are limited for most AKR1B1 inhibitors due to adverse effects of cross-inhibition with other AKRs. Here, we report an atypical competitive binding and inhibitory effect of tolrestat on the thermostable AKR Tm1743 from Thermotoga maritima. Analysis of the Tm1743 crystal structure in complex with tolrestat alone and epalrestat-NADP(+) shows that tolrestat, but not epalrestat, binding triggers dramatic conformational changes in the anionic site and cofactor binding pocket that prevents accommodation of NADP(+) . Enzymatic and molecular dynamics simulation analyses further confirm tolrestat as a competitive inhibitor of Tm1743.
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Tolrestat acts atypically as a competitive inhibitor of the thermostable aldo-keto reductase Tm1743 from Thermotoga maritima.,Zhang C, Min Z, Liu X, Wang C, Wang Z, Shen J, Tang W, Zhang X, Liu D, Xu X FEBS Lett. 2020 Feb;594(3):564-580. doi: 10.1002/1873-3468.13630. Epub 2019 Oct, 17. PMID:31573681<ref>PMID:31573681</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6ky6" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Liu, X M]]
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[[Category: Thermotoga maritima MSB8]]
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[[Category: Min, Z Z]]
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[[Category: Liu XM]]
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[[Category: Tang, W R]]
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[[Category: Min ZZ]]
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[[Category: Wang, C]]
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[[Category: Tang WR]]
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[[Category: Zhang, C Y]]
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[[Category: Wang C]]
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[[Category: Aldo-ketone reductase]]
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[[Category: Zhang CY]]
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[[Category: Competitive inhibitor]]
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[[Category: Epalrestat]]
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[[Category: Oxidoreductase]]
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[[Category: Tolrestat]]
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Current revision

Crystal structure of a thermostable aldo-keto reductase Tm1743 in complexs with inhibitor epalrestat in space group P3221cc

PDB ID 6ky6

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