5AGD

An inactive (D125N) variant of the catalytic domain, BcGH76, of Bacillus circulans Aman6 in complex with alpha-1,6-mannopentaose

Summary for 5AGD

• Entry DOI: 10.2210/pdb5agd/pdb
• Related: 4D4A 4D4B 4D4C 4D4D
• Descriptor: ALPHA-1,6-MANNANASE, alpha-D-mannopyranose-(1-6)-alpha-D-mannopyranose-(1-6)-alpha-D-mannopyranose-(1-6)-alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose, alpha-D-mannopyranose, ... (4 entities in total)
• Functional Keywords: hydrolase, alpha-mannanase, mannanase, glycoside hydrolase, gh76, cazy, mannan, enzyme-carbohydrate interaction, glycosidase inhibition, quantum mechanics, transition state
• Biological source: BACILLUS CIRCULANS
• Total number of polymer chains: 2
• Total formula weight: 83877.50

Authors

Thompson, A.J.,Speciale, G.,Iglesias-Fernandez, J.,Hakki, Z.,Belz, T.,Cartmell, A.,Spears, R.J.,Chandler, E.,Temple, M.J.,Stepper, J.,Gilbert, H.J.,Rovira, C.,Williams, S.J.,Davies, G.J. (deposition date: 2015-01-29, release date: 2015-03-25, Last modification date: 2024-05-01)

Primary citation

Thompson, A.J.,Speciale, G.,Iglesias-Fernandez, J.,Hakki, Z.,Belz, T.,Cartmell, A.,Spears, R.J.,Chandler, E.,Temple, M.J.,Stepper, J.,Gilbert, H.J.,Rovira, C.,Williams, S.J.,Davies, G.J.
Evidence for a Boat Conformation at the Transition State of Gh76 Alpha-1,6-Mannanases- Key Enzymes in Bacterial and Fungal Mannoprotein Metabolism
Angew.Chem.Int.Ed.Engl., 54:5378-, 2015

PubMed Abstract: α-Mannosidases and α-mannanases have attracted attention for the insight they provide into nucleophilic substitution at the hindered anomeric center of α-mannosides, and the potential of mannosidase inhibitors as cellular probes and therapeutic agents. We report the conformational itinerary of the family GH76 α-mannanases studied through structural analysis of the Michaelis complex and synthesis and evaluation of novel aza/imino sugar inhibitors. A Michaelis complex in an (O) S2 conformation, coupled with distortion of an azasugar in an inhibitor complex to a high energy B2,5 conformation are rationalized through ab initio QM/MM metadynamics that show how the enzyme surface restricts the conformational landscape of the substrate, rendering the B2,5 conformation the most energetically stable on-enzyme. We conclude that GH76 enzymes perform catalysis using an itinerary that passes through (O) S2 and B2,5 (≠) conformations, information that should inspire the development of new antifungal agents.

PubMed: 25772148
DOI: 10.1002/ANIE.201410502

Experimental method

X-RAY DIFFRACTION (1.2 Å)