5ne5
Crystal structure of family 47 alpha-1,2-mannosidase from Caulobacter K31 strain in complex with kifunensineCrystal structure of family 47 alpha-1,2-mannosidase from Caulobacter K31 strain in complex with kifunensine
Structural highlights
FunctionPublication Abstract from PubMedThe varied yet family-specific conformational pathways utilized by individual glycoside hydrolases (GHs) offer a tantalising prospect for the design of tight 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 selective for GH family 47 inverting a-mannosidases. Here we show, through quantum mechanical approaches, that kifunensine is restrained to a 'ring-flipped' 1C4 conformation with another accessible, but higher-energy, region around the 1,4B conformation. The conformations of kifunensine in complex with a range of GH47 enzymes including an atomic level (1 A) resolution structure of kifunensine with Caulobacter sp. CkGH47 reported herein, and on GH family 38 and 92 a-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. Conformational analysis of the mannosidase inhibitor kifunensine: a quantum mechanical and structural approach.,Males A, Raich L, Williams SJ, Rovira C, Davies GJ Chembiochem. 2017 May 11. doi: 10.1002/cbic.201700166. PMID:28493500[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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