Structural basis of the inhibition of Golgi alpha-mannosidase II by mannostatin A and the role of the thiomethyl moiety in ligand-protein interactions.

ABSTRACT: The X-ray crystal structures of mannose trimming enzyme drosophila Golgi alpha-mannosidase II (dGMII) complexed with the inhibitors mannostatin A (1) and an N-benzyl analogue (2) have been determined. Molecular dynamics simulations and NMR studies have shown that the five-membered ring of mannostatin A is rather flexible occupying pseudorotational itineraries between 2T3 and 5E, and 2T3 and 4E. In the bound state, mannostatin A adopts a 2T1 twist envelope conformation, which is not significantly populated in solution. Possible conformations of the mannosyl oxacarbenium ion and an enzyme-linked intermediate have been compared to the conformation of mannostatin A in the cocrystal structure with dGMII. It has been found that mannostatin A best mimics the covalent linked mannosyl intermediate,

SUBMITTER: Kawatkar SP 

PROVIDER: S-EPMC2553320 | biostudies-literature | 2006 Jun

REPOSITORIES: biostudies-literature