PDBsum entry 2v3e

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Hydrolase PDB id
Protein chain
498 a.a.
NND ×2
PO4 ×2
Waters ×1004

References listed in PDB file
Key reference
Title Crystal structures of complexes of n-Butyl- And n-Nonyl-Deoxynojirimycin bound to acid-Beta -Glucosidase: insights into the mechanism of chemical chaperone action in gaucher disease.
Authors B.Brumshtein, H.M.Greenblatt, T.D.Butters, Y.Shaaltiel, D.Aviezer, I.Silman, A.H.Futerman, J.L.Sussman.
Ref. J Biol Chem, 2007, 282, 29052. [DOI no: 10.1074/jbc.M705005200]
PubMed id 17666401
Gaucher disease is caused by mutations in the gene encoding acid-beta-glucosidase (GlcCerase), resulting in glucosylceramide (GlcCer) accumulation. The only currently-available orally-administered treatment for Gaucher disease is N-butyl-deoxynojirimycin (Zavescatrade mark, NB-DNJ), which partially inhibits GlcCer synthesis, thus reducing levels of GlcCer accumulation. NB-DNJ also acts as a chemical chaperone for GlcCerase, although at a different concentration to that required to completely inhibit GlcCer synthesis. We now report the crystal structures, at 2A resolution, of complexes of NB-DNJ and N-nonyl-deoxynojirimycin (NN-DNJ) with recombinant human GlcCerase, expressed in cultured plant cells. Both inhibitors bind at the active site of GlcCerase, with the imino-sugar moiety making hydrogen bonds to side chains of active-site residues. The alkyl chains of NB-DNJ and NN-DNJ are oriented towards the entrance of the active site where they undergo hydrophobic interactions. Based on these structures, we make a number of predictions concerning (i) involvement of loops adjacent to the active site in the catalytic process, (ii) the nature of nucleophilic attack by Glu340, and (iii) the role of a conserved water molecule located in a solvent cavity adjacent to the active site. Together, these results have significance for understanding the mechanism of action of GlcCerase, and the mode of GlcCerase chaperoning by imino sugars.
Figure 2.
FIGURE 2. Comparison of binding of non-covalent inhibitors to GlcCerase. A, NN-DNJ/pGlcCerase. B, NB-DNJ/pGlcCerase. C, IFG/DG-Cerezyme. Green lines represent hydrogen bonds and red lines hydrophobic interactions. L1, loop 1 (residues 341-350); L2, loop 2 (residues 393-396); L3, loop 3 (residues 312-319). 314(B) in panel A corresponds to the side chain of a symmetrically related molecule.
Figure 4.
FIGURE 4. Conformations of the loops at the entrance to the active site. The loops in GlcCerase occur in a number of conformations, but only two are shown for clarity, in yellow and green; these conformations give the most pronounced changes in the entrance to the active site. Tyr-313, which may play a role in the catalytic mechanism, is indicated. The catalytic residues are shown as red sticks.
The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 29052-0) copyright 2007.
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