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1y7v
From Proteopedia
| 1y7v, resolution 2.40Å () | |||||||||
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| Sites: | , , , , , , , , , , , , , , , , , and | ||||||||
| Ligands: | , , | ||||||||
| Gene: | GBA, GC (Homo sapiens) | ||||||||
| Activity: | Glucosylceramidase, with EC number 3.2.1.45 | ||||||||
| Related: | 1ogs | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB, TOPSAN | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
X-ray structure of human acid-beta-glucosidase covalently bound to conduritol B epoxide
(see also Treatment of Gaucher disease)
Gaucher disease is an inherited metabolic disorder caused by mutations in the lysosomal enzyme acid-beta-glucosidase (GlcCerase). We recently determined the x-ray structure of GlcCerase to 2.0 A resolution (Dvir, H., Harel, M., McCarthy, A. A., Toker, L., Silman, I., Futerman, A. H., and Sussman, J. L. (2003) EMBO Rep.4, 704-709) and have now solved the structure of Glc-Cerase conjugated with an irreversible inhibitor, conduritol-B-epoxide (CBE). The crystal structure reveals that binding of CBE to the active site does not induce a global conformational change in GlcCerase and confirms that Glu340 is the catalytic nucleophile. However, only one of two alternative conformations of a pair of flexible loops (residues 345-349 and 394-399) located at the entrance to the active site in native GlcCerase is observed in the GlcCerase-CBE structure, a conformation in which the active site is accessible to CBE. Analysis of the dynamics of these two alternative conformations suggests that the two loops act as a lid at the entrance to the active site. This possibility is supported by a cluster of mutations in loop 394-399 that cause Gaucher disease by reducing catalytic activity. Moreover, in silico mutational analysis demonstrates that all these mutations stabilize the conformation that limits access to the active site, thus providing a mechanistic explanation of how mutations in this loop result in Gaucher disease.
X-ray structure of human acid-beta-glucosidase covalently bound to conduritol-B-epoxide. Implications for Gaucher disease., Premkumar L, Sawkar AR, Boldin-Adamsky S, Toker L, Silman I, Kelly JW, Futerman AH, Sussman JL, J Biol Chem. 2005 Jun 24;280(25):23815-9. Epub 2005 Apr 6. PMID:15817452
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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About this Structure
1Y7V is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
1) X-ray structure of human acid-beta-glucosidase covalently bound to conduritol-B-epoxide. Implications for Gaucher disease., Premkumar L, Sawkar AR, Boldin-Adamsky S, Toker L, Silman I, Kelly JW, Futerman AH, Sussman JL, J Biol Chem. 2005 Jun 24;280(25):23815-9. Epub 2005 Apr 6. PMID:15817452
2) Acetylcholinesterase in motion: visualizing conformational changes in crystal structures by a morphing procedure., Zeev-Ben-Mordehai T, Silman I, Sussman JL., Biopolymers. 2003 Mar;68(3):395-406. PMID:12601798
Page seeded by OCA on Sun Jul 6 12:04:55 2008
Categories: Glucosylceramidase | Homo sapiens | Single protein | Boldin-Adamsky, S. | Futerman, A H. | ISPC, Israel Structural Proteomics Center. | Kelly, J W. | Premkumar, L. | Sawkar, A R. | Silman, I. | Sussman, J L. | Toker, L. | Alternative initiation | Cerezyme | Disease mutation | Gaucher disease | Glucocerebrosidase | Glucosidase | Glycoprotein | Glycosidase | Hydrolase | ISPC | Israel Structural Proteomics Center | Lysosome | Membrane | Pharmaceutical | Polymorphism | Signal | Sphingolipid metabolism | Structural genomic
