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1016 a.a.
_ZN
Key reference
DOI no: 10.1002/prot.21850 Proteins 71:1484-1496 (2008) PubMed id: 18076078
Binding of sulfonium-ion analogues of di-epi-swainsonine and 8-epi-lentiginosine to Drosophila Golgi alpha-mannosidase II: The role of water in inhibitor binding. N.S.Kumar, D.A.Kuntz, X.Wen, B.M.Pinto, D.R.Rose. ABSTRACT
Retaining glycosidases operate by a two-step catalytic mechanism in which the transition states are characterized by buildup of a partial positive charge at the anomeric center. Sulfonium-ion analogues of the naturally occurring glycosidase inhibitors, swainsonine and 8-epi-lentiginosine, in which the bridgehead nitrogen atom is replaced by a sulfonium-ion, were synthesized in order to test the hypothesis that a sulfonium salt carrying a permanent positive charge would be an effective glycosidase inhibitor. Initial prediction based on computational docking indicated three plausible binding modes to Drosophila Golgi alpha-mannosidase II (dGMII), the most likely being close to that of swainsonine. Observation of the binding of di-epi-thioswainsonine and 8-epi-thiolentiginosine to dGMII from crystallographic data, however, revealed an orientation different from swainsonine in the active site. Screening these two compounds against dGMII shows that they are inhibitors with IC(50) values of 2.0 and 0.014 mM, respectively. This dramatic difference in affinity between the two compounds, which differ by only one hydroxyl group, is rationalized in terms of bound water molecules and the water molecule substructure in the active site, as identified by comparison of high resolution X-ray crystal structures of several dGMII-inhibitor complexes.
Selected figure(s)
Figure 1.
Figure 1. Three predicted binding modes of compound 16 in the active site of dGMII from docking calculations: The zinc ion is shown as a magenta ball and the relevant side-chains as sticks. The calculated structure is superimposed on the crystal structure of swainsonine (6, pink) in the active site of dGMII.Figure 6.
Figure 6. Comparison of electron density in the region around Arg228. The presence of water density at the position of Wat467 in the 17 structure (top) and its absence in the 16 structure bottom is unambiguous. The electron density is a 2Fobs-Fcalc map contoured at 1 sigma.The above figures are reprinted by permission from John Wiley & Sons, Inc.: Proteins (2008, 71, 1484-1496) copyright 2008. Figures were selected by an automated process.
Literature references that cite this PDB file's key reference
PubMed id Reference
19101978 D.A.Kuntz, W.Zhong, J.Guo, D.R.Rose, and G.J.Boons (2009).
The Molecular Basis of Inhibition of Golgi alpha-Mannosidase II by Mannostatin A.Chembiochem, 10, 268-277.
PDB codes: 3dx0 3dx1 3dx2 3dx3 3dx4 The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.
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