4ccc | pdb_00004ccc

STRUCTURE OF MOUSE GALACTOCEREBROSIDASE WITH 4NBDG: ENZYME-SUBSTRATE COMPLEX

spinqualitylabelsall models 4ccc, resolution 2.09Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ccc is a 1 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 147, CA, NAG Related: 4ccd, 4cce Activity: Galactosylceramidase, with EC number 3.2.1.46 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [GALC_MOUSE] Defects in Galc are the cause of the 'twitcher' phenotype; an autosomal recessive leukodystrophy similar to the human disease (Krabbe disease). This deficiency results in the insufficient catabolism of several galactolipids that are important in the production of normal myelin. Function [GALC_MOUSE] Hydrolyzes the galactose ester bonds of galactosylceramide, galactosylsphingosine, lactosylceramide, and monogalactosyldiglyceride. Enzyme with very low activity responsible for the lysosomal catabolism of galactosylceramide, a major lipid in myelin, kidney and epithelial cells of small intestine and colon. Publication Abstract from PubMed Glycosphingolipids are ubiquitous components of mammalian cell membranes, and defects in their catabolism by lysosomal enzymes cause a diverse array of diseases. Deficiencies in the enzyme beta-galactocerebrosidase (GALC) cause Krabbe disease, a devastating genetic disorder characterized by widespread demyelination and rapid, fatal neurodegeneration. Here, we present a series of high-resolution crystal structures that illustrate key steps in the catalytic cycle of GALC. We have captured a snapshot of the short-lived enzyme-substrate complex illustrating how wild-type GALC binds a bona fide substrate. We have extensively characterized the enzyme kinetics of GALC with this substrate and shown that the enzyme is active in crystallo by determining the structure of the enzyme-product complex following extended soaking of the crystals with this same substrate. We have also determined the structure of a covalent intermediate that, together with the enzyme-substrate and enzyme-product complexes, reveals conformational changes accompanying the catalytic steps and provides key mechanistic insights, laying the foundation for future design of pharmacological chaperones. Structural snapshots illustrate the catalytic cycle of beta-galactocerebrosidase, the defective enzyme in Krabbe disease.,Hill CH, Graham SC, Read RJ, Deane JE Proc Natl Acad Sci U S A. 2013 Dec 2. PMID:24297913 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Galactosylceramidase

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