6FAM
Structure of the GH99 endo-alpha-mannanase from Bacteroides xylanisolvens in complex with mannose-alpha-1,3-2-aminodeoxymannojirimycin
Summary for 6FAM
| Entry DOI | 10.2210/pdb6fam/pdb |
| Related | 6FAR |
| Descriptor | Glycosyl hydrolase family 71, ACETATE ION, alpha-D-mannopyranose, ... (5 entities in total) |
| Functional Keywords | complex, gh99, hydrolase |
| Biological source | Bacteroides xylanisolvens XB1A |
| Total number of polymer chains | 1 |
| Total formula weight | 44334.98 |
| Authors | Fernandes, P.Z.,Petricevic, M.,Sobala, L.F.,Davies, G.J.,Williams, S.J. (deposition date: 2017-12-15, release date: 2018-03-21, Last modification date: 2024-01-17) |
| Primary citation | Fernandes, P.Z.,Petricevic, M.,Sobala, L.,Davies, G.J.,Williams, S.J. Exploration of Strategies for Mechanism-Based Inhibitor Design for Family GH99 endo-alpha-1,2-Mannanases. Chemistry, 24:7464-7473, 2018 Cited by PubMed Abstract: endo-α-1,2-Mannosidases and -mannanases, members of glycoside hydrolase family 99 (GH99), cleave α-Glc/Man-1,3-α-Man-OR structures within mammalian N-linked glycans and fungal α-mannan, respectively. They are proposed to act through a two-step mechanism involving a 1,2-anhydrosugar "epoxide" intermediate incorporating two conserved catalytic carboxylates. In the first step, one carboxylate acts as a general base to deprotonate the 2-hydroxy group adjacent to the fissile glycosidic bond, and the other provides general acid assistance to the departure of the aglycon. We report herein the synthesis of two inhibitors designed to interact with either the general base (α-mannosyl-1,3-(2-aminodeoxymannojirimycin), Man2NH DMJ) or the general acid (α-mannosyl-1,3-mannoimidazole, ManManIm). Modest affinities were observed for an endo-α-1,2-mannanase from Bacteroides thetaiotaomicron. Structural studies revealed that Man2NH DMJ binds like other iminosugar inhibitors, which suggests that the poor inhibition shown by this compound is not a result of a failure to achieve the expected interaction with the general base, but rather the reduction in basicity of the endocyclic nitrogen caused by introduction of a vicinal, protonated amine at C2. ManManIm binds with the imidazole headgroup distorted downwards, a result of an unfavourable interaction with a conserved active site tyrosine. This study has identified important limitations associated with mechanism-inspired inhibitor design for GH99 enzymes. PubMed: 29508463DOI: 10.1002/chem.201800435 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.13 Å) |
Structure validation
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