Journal article
An atypical interaction explains the high-affinity of a non-hydrolyzable S-linked 1,6-α-mannanase inhibitor
T Belz, Y Jin, J Coines, C Rovira, GJ Davies, SJ 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 Amicus Therapeutics
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).