7UZ1

Structure of beta-glycosidase from Sulfolobus solfataricus in complex with C5a-bromo-valienide.

Summary for 7UZ1

• Entry DOI: 10.2210/pdb7uz1/pdb
• Descriptor: Beta-galactosidase, (1R,2S,3R,4R)-5-bromo-6-(hydroxymethyl)cyclohex-5-ene-1,2,3,4-tetrol, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: covalent inhibition, glycoside hydrolase, hydrolase
• Biological source: Saccharolobus solfataricus
• Total number of polymer chains: 2
• Total formula weight: 114225.12

Authors

Danby, P.M.,Jeong, A.,Sim, L.,Sweeney, R.P.,Wardman, J.F.,Karimi, R.,Geissner, A.,Worrall, L.J.,Strynadka, N.C.J.,Withers, S.G. (deposition date: 2022-05-08, release date: 2023-04-05, Last modification date: 2024-10-30)

Primary citation

Danby, P.M.,Jeong, A.,Sim, L.,Sweeney, R.P.,Wardman, J.F.,Karimi, R.,Geissner, A.,Worrall, L.J.,Reid, J.P.,Strynadka, N.C.J.,Withers, S.G.
Vinyl Halide-Modified Unsaturated Cyclitols are Mechanism-Based Glycosidase Inhibitors.
Angew.Chem.Int.Ed.Engl., 62:e202301258-e202301258, 2023

PubMed Abstract: Suitably configured allyl ethers of unsaturated cyclitols act as substrates of β-glycosidases, reacting via allylic cation transition states. Incorporation of halogens at the vinylic position of these carbasugars, along with an activated leaving group, generates potent inactivators of β-glycosidases. Enzymatic turnover of these halogenated cyclitols (F, Cl, Br) displayed a counter-intuitive trend wherein the most electronegative substituents yielded the most labile pseudo-glycosidic linkages. Structures of complexes with the Sulfolobus β-glucosidase revealed similar enzyme-ligand interactions to those seen in complexes with a 2-fluorosugar inhibitor, the lone exception being displacement of tyrosine 322 from the active site by the halogen. Mutation of Y322 to Y322F largely abolished glycosidase activity, consistent with lost interactions at O5, but minimally affected (7-fold) rates of carbasugar hydrolysis, yielding a more selective enzyme for unsaturated cyclitol ether hydrolysis.

PubMed: 36940280
DOI: 10.1002/anie.202301258

Experimental method

X-RAY DIFFRACTION (1.58 Å)