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2v3f
From Proteopedia
| 2v3f, resolution 1.95Å () | |||||||||
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| Sites: | , , , , , , , , , , , , , , , , , , , and | ||||||||
| Ligands: | , | ||||||||
| Non-Standard Residues: | , , | ||||||||
| Activity: | Glucosylceramidase, with EC number 3.2.1.45 | ||||||||
| Domains: | Glyco_hydro_30, COG5520 | ||||||||
| Related: | 1ogs, 1y7v, 2f61, 2j25, 2v3d, 2v3e | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
ACID-BETA-GLUCOSIDASE PRODUCED IN CARROT CELLS
(see also Treatment of Gaucher disease)
Gaucher's disease, a lysosomal storage disorder caused by mutations in the gene encoding glucocerebrosidase (GCD), is currently treated by enzyme replacement therapy using recombinant GCD (Cerezyme) expressed in Chinese hamster ovary (CHO) cells. As complex glycans in mammalian cells do not terminate in mannose residues, which are essential for the biological uptake of GCD via macrophage mannose receptors in human patients with Gaucher's disease, an in vitro glycan modification is required in order to expose the mannose residues on the glycans of Cerezyme. In this report, the production of a recombinant human GCD in a carrot cell suspension culture is described. The recombinant plant-derived GCD (prGCD) is targeted to the storage vacuoles, using a plant-specific C-terminal sorting signal. Notably, the recombinant human GCD expressed in the carrot cells naturally contains terminal mannose residues on its complex glycans, apparently as a result of the activity of a special vacuolar enzyme that modifies complex glycans. Hence, the plant-produced recombinant human GCD does not require exposure of mannose residues in vitro, which is a requirement for the production of Cerezyme. prGCD also displays a level of biological activity similar to that of Cerezyme produced in CHO cells, as well as a highly homologous high-resolution three-dimensional structure, determined by X-ray crystallography. A single-dose toxicity study with prGCD in mice demonstrated the absence of treatment-related adverse reactions or clinical findings, indicating the potential safety of prGCD. prGCD is currently undergoing clinical studies, and may offer a new and alternative therapeutic option for Gaucher's disease.
Production of glucocerebrosidase with terminal mannose glycans for enzyme replacement therapy of Gaucher's disease using a plant cell system., Shaaltiel Y, Bartfeld D, Hashmueli S, Baum G, Brill-Almon E, Galili G, Dym O, Boldin-Adamsky SA, Silman I, Sussman JL, Futerman AH, Aviezer D, Plant Biotechnol J. 2007 Sep;5(5):579-90. Epub 2007 May 24. PMID:17524049
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Three-dimensional structure of recombinant plant-derived glucocerebrosidase (prGCD) consists of . Domain I (residues 1–27 and 384–414, colored pink) comprises a 3-stranded anti-parallel β-sheet flanked by a perpendicular amino-terminal strand. Domain II (residues 30–75 and 431–497, colored lime) consists of two β-sheets. Domain III (residues 76–381 and 416–430, colored red) is a (β/α)8 TIM barrel. with molecule BTB is shown.
of prGCD with both Cerezyme® (1ogs) and Cerezyme® covalently modified by an irreversible inhibitor, conduritol-B-epoxide (1y7v, colored yellow), revealed highly significant structural identity. The RMSD values for Cα atoms of these structures were of 0.64 and 0.60 Å, respectively. Moreover, there was strict conservation of the .
About this Structure
2V3F is a 2 chains structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
- Shaaltiel Y, Bartfeld D, Hashmueli S, Baum G, Brill-Almon E, Galili G, Dym O, Boldin-Adamsky SA, Silman I, Sussman JL, Futerman AH, Aviezer D. Production of glucocerebrosidase with terminal mannose glycans for enzyme replacement therapy of Gaucher's disease using a plant cell system. Plant Biotechnol J. 2007 Sep;5(5):579-90. Epub 2007 May 24. PMID:17524049
Page seeded by OCA on Tue Feb 17 20:29:26 2009
Proteopedia Page Contributors and Editors (what is this?)
Categories: Glucosylceramidase | Homo sapiens | Aviezer, D. | Bartfeld, D. | Baum, G. | Boldin-Adamsky, S A. | Brill-Almon, E. | Dym, O. | Futerman, A H. | Galili, G. | Hashmueli, S. | Ispc, Israel Structural Proteomics Center. | ISPC, Israel Structural Proteomics Center. | ISPC | Shaaltiel, Y. | Silman, I. | Sussman, J L. | Acid-beta-glucosidase | Alternative initiation | Alternative splicing | Disease mutation | Gaucher disease | Glycoprotein | Glycosidase | Hydrolase | Lipid metabolism | Lysosome | Membrane | N-butyl-deoxynojirimycin | Pharmaceutical | Polymorphism | Sphingolipid metabolism
