Combined inhibitor free-energy landscape and structural analysis reports on the mannosidase conformational coordinate

TY - JOUR

T1 - Combined inhibitor free-energy landscape and structural analysis reports on the mannosidase conformational coordinate

AU - Williams, Rohan J

AU - Iglesias-Fernández, Javier

AU - Stepper, Judith

AU - Jackson, Adam

AU - Thompson, Andrew J

AU - Lowe, Elisabeth C

AU - White, Jonathan M

AU - Gilbert, Harry J

AU - Rovira, Carme

AU - Davies, Gideon J

AU - Williams, Spencer J

N1 - © 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

PY - 2014/1/20

Y1 - 2014/1/20

N2 - Mannosidases catalyze the hydrolysis of a diverse range of polysaccharides and glycoconjugates, and the various sequence-based mannosidase families have evolved ingenious strategies to overcome the stereoelectronic challenges of mannoside chemistry. Using a combination of computational chemistry, inhibitor design and synthesis, and X-ray crystallography of inhibitor/enzyme complexes, it is demonstrated that mannoimidazole-type inhibitors are energetically poised to report faithfully on mannosidase transition-state conformation, and provide direct evidence for the conformational itinerary used by diverse mannosidases, including β-mannanases from families GH26 and GH113. Isofagomine-type inhibitors are poor mimics of transition-state conformation, owing to the high energy barriers that must be crossed to attain mechanistically relevant conformations, however, these sugar-shaped heterocycles allow the acquisition of ternary complexes that span the active site, thus providing valuable insight into active-site residues involved in substrate recognition.

AB - Mannosidases catalyze the hydrolysis of a diverse range of polysaccharides and glycoconjugates, and the various sequence-based mannosidase families have evolved ingenious strategies to overcome the stereoelectronic challenges of mannoside chemistry. Using a combination of computational chemistry, inhibitor design and synthesis, and X-ray crystallography of inhibitor/enzyme complexes, it is demonstrated that mannoimidazole-type inhibitors are energetically poised to report faithfully on mannosidase transition-state conformation, and provide direct evidence for the conformational itinerary used by diverse mannosidases, including β-mannanases from families GH26 and GH113. Isofagomine-type inhibitors are poor mimics of transition-state conformation, owing to the high energy barriers that must be crossed to attain mechanistically relevant conformations, however, these sugar-shaped heterocycles allow the acquisition of ternary complexes that span the active site, thus providing valuable insight into active-site residues involved in substrate recognition.

U2 - 10.1002/anie.201308334

DO - 10.1002/anie.201308334

M3 - Article

C2 - 24339341

SN - 1433-7851

VL - 53

SP - 1087

EP - 1091

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

IS - 4

ER -