2F7O
Golgi alpha-mannosidase II complex with mannostatin A
Summary for 2F7O
| Entry DOI | 10.2210/pdb2f7o/pdb |
| Related | 1HTY 1HWW 1HXK 1PS3 1QWN 1QWU 1QX1 2F7P 2F7Q 2F7R |
| Descriptor | alpha-mannosidase II, 2-acetamido-2-deoxy-beta-D-glucopyranose, ZINC ION, ... (7 entities in total) |
| Functional Keywords | glycosyl hydrolase family 38, hydrolase |
| Biological source | Drosophila melanogaster (fruit fly) |
| Total number of polymer chains | 1 |
| Total formula weight | 120380.62 |
| Authors | Kuntz, D.A.,Rose, D.R. (deposition date: 2005-12-01, release date: 2006-07-04, Last modification date: 2024-11-20) |
| Primary citation | Kawatkar, S.P.,Kuntz, D.A.,Woods, R.J.,Rose, D.R.,Boons, G.J. Structural Basis of the Inhibition of Golgi alpha-Mannosidase II by Mannostatin A and the Role of the Thiomethyl Moiety in Ligand-Protein Interactions. J.Am.Chem.Soc., 128:8310-8319, 2006 Cited by PubMed 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, which adopts a 1S5 skew boat conformation. The thiomethyl group, which is critical for high affinity, superimposes with the C-6 hydroxyl of the covalent linked intermediate. This functionality is able to make a number of additional polar and nonpolar interactions increasing the affinity for dGMII. Furthermore, the X-ray structures show that the environment surrounding the thiomethyl group of 1 is remarkably similar to the arrangements around the methionine residues in the protein. Collectively, our studies contradict the long held view that potent inhibitors of glycosidases must mimic an oxacarbenium ion like transition state. PubMed: 16787095DOI: 10.1021/ja061216p PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.43 Å) |
Structure validation
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