Journal article
An atypical interaction explains the high-affinity of a non-hydrolyzable S-linked 1,6-alpha-mannanase inhibitor
Tyson Belz, Yi Jin, Joan Coines, Carme Rovira, Gideon J Davies, Spencer J Williams
CHEMICAL COMMUNICATIONS | ROYAL SOC CHEMISTRY | Published : 2017
DOI: 10.1039/c7cc04977c
Abstract
The non-hydrolyzable S-linked azasugars, 1,6-α-mannosylthio- and 1,6-α-mannobiosylthioisofagomine, were synthesized and shown to bind with high affinity to a family 76 endo-1,6-α-mannanase from Bacillus circulans. X-ray crystallography showed an atypical interaction of the isofagomine nitrogen with the catalytic acid/base. Molecular dynamics simulations reveal that the atypical binding results from sulfur perturbing the most stable form away from the nucleophile interaction preferred for the O-linked congener.
Grants
Awarded by European Research Council
Awarded by Australian Research Council
Awarded by Spanish Ministry of Economy, Industry and Competitiveness (MINECO)
Awarded by Generalitat de Catalunya-AGAUR
Awarded by Biotechnology and Biological Sciences Research Council
Funding Acknowledgements
We are supported by the Royal Society (Ken Murray Research professorship to G. J. D.), the European Research Council (ERC-2012-AdG-32294 "Glycopoise'' to G. J. D. and Y. J.), the Australian Research Council (FT130100103) (S. J. W.), the Spanish Ministry of Economy, Industry and Competitiveness (MINECO, CTQ2014-55174-P) (C. R. and J. C.) and Generalitat de Catalunya-AGAUR (2014SGR-987) (C. R.). We thank Diamond Light Source for access to beamline I02 and I04 (mx-13587), BSC-CNS for computer resources and technical support at MareNostrum (RES-QCM-2016-3-0017), and Amicus Therapeutics. J. C. thanks MINECO for a PhD scholarship (FPI).