Journal article
Contribution of shape and charge to the inhibition of a family GH99 endo-α-1,2-mannanase
M Petricevic, LF Sobala, PZ Fernandes, L Raich, AJ Thompson, G Bernardo-Seisdedos, O Millet, S Zhu, M Sollogoub, J Jiménez-Barbero, C Rovira, GJ Davies, SJ Williams
Journal of the American Chemical Society | AMER CHEMICAL SOC | Published : 2017
DOI: 10.1021/jacs.6b10075
Abstract
Inhibitor design incorporating features of the reaction coordinate and transition-state structure has emerged as a powerful approach for the development of enzyme inhibitors. Such inhibitors find use as mechanistic probes, chemical biology tools, and therapeutics. Endo-α-1,2-mannosidases and endo-α-1,2-mannanases, members of glycoside hydrolase family 99(GH99), are interesting targets for inhibitor development as they play key roles in N-glycan maturation and microbiotal yeast mannan degradation, respectively. These enzymes are proposed to act via a 1,2-anhydrosugar "epoxide" mechanism that proceeds through an unusual conformational itinerary. Here, we explore how shape and charge contribute..
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Grants
Awarded by European Commission
Funding Acknowledgements
We thank the Australian Research Council (FT130100103; DP120101396), the BBSRC (BB/G016127/1) and the ERC (ERC-2012-AdG-322942), the Spanish Ministry of Economy and Competitiveness (CTQ2014-55174, CTQ2015-64597-C2-1P, CTQ2015-68756-R) and the Generalitat de Catalunya (2014SGR-987). We thank Diamond Light Source for access to beamlines i02, i04,i04-1, and i24 (mx-9948) that contributed to the results presented here. We are grateful to Sivanandam Veeramuthu for his help with NMR. In-house crystal screening and testing was performed on X-ray equipment provided, in part, by the Wellcome Trust. The authors gratefully acknowledge the computer resources at MareNostrum and the technical support provided by BSC-CNS (RES-QCM-2016-3-00017). L.R. thanks the University of Barcelona for an APIF predoctoral fellowship.