2V3D

acid-beta-glucosidase with N-butyl-deoxynojirimycin

Summary for 2V3D

• Entry DOI: 10.2210/pdb2v3d/pdb
• Related: 1OGS 1Y7V 2F61 2J25 2V3E 2V3F
• Descriptor: GLUCOSYLCERAMIDASE, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-3)]2-acetamido-2-deoxy-beta-D-glucopyranose, SULFATE ION, ... (6 entities in total)
• Functional Keywords: acid-beta-glucosidase, n-butyl-deoxynojirimycinalternative initiation, sphingolipid metabolism, gaucher disease, disease mutation, lipid metabolism, polymorphism, glycoprotein, pharmaceutical, n-butyl-deoxynojirimycin, alternative splicing, membrane, lysosome, hydrolase, glycosidase
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 2
• Total formula weight: 116072.20

Authors

Brumshtein, B.,Greenblatt, H.M.,Butters, T.D.,Shaaltiel, Y.,Aviezer, D.,Silman, I.,Futerman, A.H.,Sussman, J.L. (deposition date: 2007-06-17, release date: 2007-08-14, Last modification date: 2023-12-13)

Primary citation

Brumshtein, B.,Greenblatt, H.M.,Butters, T.D.,Shaaltiel, Y.,Aviezer, D.,Silman, I.,Futerman, A.H.,Sussman, J.L.
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.
J.Biol.Chem., 282:29052-, 2007

PubMed Abstract: 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 (Zavesca, 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 than 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 toward 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 Glu-340, 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.

PubMed: 17666401
DOI: 10.1074/JBC.M705005200

Experimental method

X-RAY DIFFRACTION (1.96 Å)