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Revealing the mechanism for covalent inhibition of glycoside hydrolases by carbasugars at an atomic level
dc.contributor.author | Ren, Weiwu | |
dc.contributor.author | Pengelly, Robert | |
dc.contributor.author | Farren-Dai, Marco | |
dc.contributor.author | Shamsi Kazem Abadi, Saeideh | |
dc.contributor.author | Oehler, Verena | |
dc.contributor.author | Akintola, Oluwafemi | |
dc.contributor.author | Draper, Jason | |
dc.contributor.author | Meanwell, Michael | |
dc.contributor.author | Chakladar, Saswati | |
dc.contributor.author | Świderek, Katarzyna | |
dc.contributor.author | Moliner, Vicent | |
dc.contributor.author | Britton, Robert | |
dc.contributor.author | Gloster, Tracey M. | |
dc.contributor.author | Bennet, Andrew J. | |
dc.date.accessioned | 2018-11-26T11:17:14Z | |
dc.date.available | 2018-11-26T11:17:14Z | |
dc.date.issued | 2018 | |
dc.identifier.citation | REN, Weiwu, et al. Revealing the mechanism for covalent inhibition of glycoside hydrolases by carbasugars at an atomic level. Nature communications, 2018, vol. 9, no 1, p. 3243. | ca_CA |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | http://hdl.handle.net/10234/177654 | |
dc.description.abstract | Mechanism-based glycoside hydrolase inhibitors are carbohydrate analogs that mimic the natural substrate’s structure. Their covalent bond formation with the glycoside hydrolase makes these compounds excellent tools for chemical biology and potential drug candidates. Here we report the synthesis of cyclohexene-based α-galactopyranoside mimics and the kinetic and structural characterization of their inhibitory activity toward an α-galactosidase from Thermotoga maritima (TmGalA). By solving the structures of several enzyme-bound species during mechanism-based covalent inhibition of TmGalA, we show that the Michaelis complexes for intact inhibitor and product have half-chair (2H3) conformations for the cyclohexene fragment, while the covalently linked intermediate adopts a flattened half-chair (2H3) conformation. Hybrid QM/MM calculations confirm the structural and electronic properties of the enzyme-bound species and provide insight into key interactions in the enzyme-active site. These insights should stimulate the design of mechanism-based glycoside hydrolase inhibitors with tailored chemical properties | ca_CA |
dc.format.extent | 12 p. | ca_CA |
dc.format.mimetype | application/pdf | ca_CA |
dc.language.iso | eng | ca_CA |
dc.publisher | Nature Research | ca_CA |
dc.relation.isPartOf | Nature Communications, volume 9 (2018) | ca_CA |
dc.rights | Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. © The Author(s) 2018 | ca_CA |
dc.rights | Atribución 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by-sa/4.0/ | * |
dc.title | Revealing the mechanism for covalent inhibition of glycoside hydrolases by carbasugars at an atomic level | ca_CA |
dc.type | info:eu-repo/semantics/article | ca_CA |
dc.identifier.doi | https://doi.org/10.1038/s41467-018-05702-7 | |
dc.relation.projectID | 121348-2012 ; 2017-04910 ; CTQ2015-66223-C2 ; IJCI-2016-27503 ; UJI.B2017-31 | ca_CA |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | ca_CA |
dc.relation.publisherVersion | https://www.nature.com/articles/s41467-018-05702-7 | ca_CA |
dc.type.version | info:eu-repo/semantics/publishedVersion | ca_CA |
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Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made. The images or other third party
material in this article are included in the article’s Creative Commons license, unless
indicated otherwise in a credit line to the material. If material is not included in the
article’s Creative Commons license and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from
the copyright holder. To view a copy of this license, visit http://creativecommons.org/
licenses/by/4.0/.
© The Author(s) 2018