4D4A: Structure Of The Catalytic Domain (bcgh76) Of The Bacillus Circulans Gh76 Alpha Mannanase, Aman6

alpha-Mannosidases and alpha-mannanases have attracted attention for the insight they provide into nucleophilic substitution at the hindered anomeric center of alpha-mannosides, and the potential of mannosidase inhibitors as cellular probes and therapeutic agents. We report the conformational itinerary of the family GH76 alpha-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 ( not equal) conformations, information that should inspire the development of new antifungal agents.
PDB ID: 4D4ADownload
MMDB ID: 128031
PDB Deposition Date: 2014/10/27
Updated in MMDB: 2015/05
Experimental Method:
x-ray diffraction
Resolution: 1.4  Å
Source Organism:
Similar Structures:
Biological Unit for 4D4A: monomeric; determined by author and by software (PISA)
Molecular Components in 4D4A
Label Count Molecule
Protein (1 molecule)
Molecule annotation
Chemicals (4 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB