6GWG

Alpha-galactosidase from Thermotoga maritima in complex with cyclohexene-based carbasugar mimic of galactose covalently linked to the nucleophile

Summary for 6GWG

• Entry DOI: 10.2210/pdb6gwg/pdb
• Related: 6GTA 6GVD 6GWF
• Descriptor: Alpha-galactosidase, SULFATE ION, (1~{S},2~{S},3~{S})-3-fluoranyl-6-(hydroxymethyl)cyclohex-5-ene-1,2,4-triol, ... (6 entities in total)
• Functional Keywords: glycoside hydrolase, galactosidase, carbohydrate processing enzyme, inhibitor, hydrolase
• Biological source: Thermotoga maritima MSB8
• Total number of polymer chains: 1
• Total formula weight: 67401.86

Authors

Gloster, T.M.,Oehler, V. (deposition date: 2018-06-24, release date: 2018-08-22, Last modification date: 2024-10-09)

Primary citation

Ren, W.,Pengelly, R.,Farren-Dai, M.,Shamsi Kazem Abadi, S.,Oehler, V.,Akintola, O.,Draper, J.,Meanwell, M.,Chakladar, S.,Swiderek, K.,Moliner, V.,Britton, R.,Gloster, T.M.,Bennet, A.J.
Revealing the mechanism for covalent inhibition of glycoside hydrolases by carbasugars at an atomic level.
Nat Commun, 9:3243-3243, 2018

PubMed Abstract: Mechanism-based glycoside hydrolase inhibitors are carbohydrate analogs that mimic the natural substrate's structure. Their covalent bond formation with the glycoside hydrolase makes these compounds excellent tools for chemical biology and potential drug candidates. Here we report the synthesis of cyclohexene-based α-galactopyranoside mimics and the kinetic and structural characterization of their inhibitory activity toward an α-galactosidase from Thermotoga maritima (TmGalA). By solving the structures of several enzyme-bound species during mechanism-based covalent inhibition of TmGalA, we show that the Michaelis complexes for intact inhibitor and product have half-chair (H) conformations for the cyclohexene fragment, while the covalently linked intermediate adopts a flattened half-chair (H) conformation. Hybrid QM/MM calculations confirm the structural and electronic properties of the enzyme-bound species and provide insight into key interactions in the enzyme-active site. These insights should stimulate the design of mechanism-based glycoside hydrolase inhibitors with tailored chemical properties.

PubMed: 30104598
DOI: 10.1038/s41467-018-05702-7

Experimental method

X-RAY DIFFRACTION (1.77 Å)