Journal article

Conformational Analysis of the Mannosidase Inhibitor Kifunensine: A Quantum Mechanical and Structural Approach

Alexandra Males, Lluis Raich, Spencer J Williams, Carme Rovira, Gideon J Davies



The varied yet family-specific conformational pathways used by individual glycoside hydrolases (GHs) offer a tantalising prospect for the design of tightly binding and specific enzyme inhibitors. A cardinal example of a GH-family-specific inhibitor, and one that finds widespread practical use, is the natural product kifunensine, which is a low-nanomolar inhibitor that is selective for GH family 47 inverting α-mannosidases. Here we show, through quantum-mechanical approaches, that kifunensine is restrained to a "ring-flipped" 1 C4 conformation with another accessible, but higher-energy, region around the 1,4 B conformation. The conformations of kifunensine in complex with a range of GH47 enzy..

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University of Melbourne Researchers


Awarded by BBSRC

Awarded by Spanish Ministry of Economy and Competitiveness

Awarded by AGAUR

Awarded by BSC-CNS

Awarded by Biotechnology and Biological Sciences Research Council

Funding Acknowledgements

We thank Diamond Light Source for access to beamline I04-1 (proposal number mx-13587), which contributed to the results presented here. G.J.D. is the Royal Society Ken Murray Research Professor. S.J.W. is an Australian Research Council Future Fellow (FT130100103). A.M. and L.R. are supported through BBSRC (BB/M011151/1) and Ajuts de Personal Investigador predoctoral en Formacio-Universitat de Barcelona (APIF-UB) PhD studentships, respectively. We thank the Spanish Ministry of Economy and Competitiveness (grant CTQ2014-55174-P to C.R.) and AGAUR (grant SGR2014-987 to C.R.), The authors gratefully acknowledge the computer resources at MareNostrum and the technical support provided by BSC-CNS (RES-QCM-2016-3-00017).