Abstract
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 enzymes-including an atomic-level resolution (1 Å) structure of kifunensine with Caulobacter sp. CkGH47 reported herein and with GH family 38 and 92 α-mannosidases-were mapped onto the kifunensine free-energy landscape. These studies revealed that kifunensine has the ability to mimic the product state of GH47 enzymes but cannot mimic any conformational states relevant to the reaction coordinate of mannosidases from other families.
Highlights
Conformations matching that of the transition state of a specific glycoside hydrolases (GHs) have been disappointing
To map the conformational reaction pathways of glycosidases leading from substrate to product via the transition state(s) have revealed that individual glycosidases are optimized to act on substrates and follow a defined conformational itinerary through a specific transition-state conformation.[2]
Given that mimicry of the enzymatic transitionstate is a powerful approach to inhibitor design and enzyme inhibition,[4] the potential exists for molecules to be designed or discovered with intrinsically-biased conformations that could act as GH family-specific enzyme inhibitors
Summary
Conformations matching that of the transition state of a specific GH have been disappointing.
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