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dc.contributor.authorRen, Weiwu
dc.contributor.authorPengelly, Robert Joseph
dc.contributor.authorFarren-Dai, Marco
dc.contributor.authorAbadi, Saeideh Shamsi Kazem
dc.contributor.authorOehler, Verena
dc.contributor.authorAkintola, Oluwafemi
dc.contributor.authorDraper, Jason
dc.contributor.authorMeanwell, Michael
dc.contributor.authorChakladar, Saswati
dc.contributor.authorŚwiderek, Katazyna
dc.contributor.authorMoliner, Vincent
dc.contributor.authorBritton, Robert
dc.contributor.authorGloster, Tracey
dc.contributor.authorBennet, Andrew
dc.identifier.citationRen , W , Pengelly , R J , Farren-Dai , M , Abadi , S S K , Oehler , V , Akintola , O , Draper , J , Meanwell , M , Chakladar , S , Świderek , K , Moliner , V , Britton , R , Gloster , T & Bennet , A 2018 , ' Revealing the mechanism for covalent inhibition of glycoside hydrolases by carbasugars at an atomic level ' , Nature Communications , vol. 9 , 3243 .
dc.identifier.otherPURE: 255285653
dc.identifier.otherPURE UUID: 2c1ce514-4978-400c-9a2c-b55d5882b6e5
dc.identifier.otherScopus: 85051629558
dc.identifier.otherWOS: 000441382000021
dc.descriptionFinancial support from the Natural Sciences and Engineering Research Council (NSERC) of Canada (AJB Discovery Grants: 121348–2012 & 2017–04910) was received. T.M.G. and V.O. are funded by a Wellcome Trust Career Development Fellowship, R.P. by Wellcome Trust ISSF, M.M. by a NSERC CGSD, M.F.-D. by a NSERC CGS-MSFSS and a GlycoNet Research Exchange Program, and R.B. by NSERC Discovery Grant and by a MSFHR Career Investigator Award. V.M. and K.Ś. thank the Spanish Ministerio de Economía y Competitividad and FEDER funds (project CTQ2015-66223-C2) and a Juan de la Cierva – Incorporación (ref. IJCI-2016-27503) contract, respectively, and Universitat Jaume I (project UJI·B2017-31).en
dc.description.abstractMechanism-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.
dc.relation.ispartofNature Communicationsen
dc.rights© The Author(s) 2018. 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
dc.subjectQH301 Biologyen
dc.subjectQD Chemistryen
dc.titleRevealing the mechanism for covalent inhibition of glycoside hydrolases by carbasugars at an atomic levelen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews.School of Biologyen
dc.contributor.institutionUniversity of St Andrews.Biomedical Sciences Research Complexen
dc.description.statusPeer revieweden

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