PDBsum entry 5agd

Hydrolase

PDB id: 5agd

Contents

Protein chains

333 a.a.

Ligands

MAN ×2

BMA-MAN-MAN-MAN-MAN ×2

Waters ×1039

References listed in PDB file

Key reference

• Title: Evidence for a boat conformation at the transition state of gh76 α-1,6-Mannanases--Key enzymes in bacterial and fungal mannoprotein metabolism.
• Authors: A.J.Thompson, G.Speciale, J.Iglesias-Fernández, Z.Hakki, T.Belz, A.Cartmell, R.J.Spears, E.Chandler, M.J.Temple, J.Stepper, H.J.Gilbert, C.Rovira, S.J.Williams, G.J.Davies.
• Ref.: Angew Chem Int Ed Engl, 2015, 54, 5378-5382. [DOI no: 10.1002/anie.201410502]
• PubMed id: 25772148

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.