Journal article

Contribution of Shape and Charge to the Inhibition of a Family GH99 endo-alpha-1,2-Mannanase

Marija Petricevic, Lukasz F Sobala, Pearl Z Fernandes, Lluis Raich, Andrew J Thompson, Ganeko Bernardo-Seisdedos, Oscar Millet, Sha Zhu, Matthieu Sollogoub, Jesus Jimenez-Barbero, Carme Rovira, Gideon J Davies, Spencer J Williams



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 contribut..

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University of Melbourne Researchers


Awarded by Australian Research Council

Awarded by BBSRC

Awarded by ERC

Awarded by Spanish Ministry of Economy and Competitiveness

Awarded by Generalitat de Catalunya

Awarded by Biotechnology and Biological Sciences Research Council

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.