4CCC
STRUCTURE OF MOUSE GALACTOCEREBROSIDASE WITH 4NBDG: ENZYME-SUBSTRATE COMPLEX
Summary for 4CCC
| Entry DOI | 10.2210/pdb4ccc/pdb |
| Related | 4CCD 4CCE |
| Descriptor | GALACTOCEREBROSIDASE, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 4-nitrophenyl beta-D-galactopyranoside, ... (6 entities in total) |
| Functional Keywords | hydrolase, krabbe disease, glycosyl hydrolase, 4-nitrophenyl-beta-d-galactopyranoside, lysosomal storage disease, enzyme- substrate complex |
| Biological source | MUS MUSCULUS (HOUSE MOUSE) |
| Cellular location | Lysosome (By similarity): P54818 |
| Total number of polymer chains | 1 |
| Total formula weight | 76432.49 |
| Authors | Hill, C.H.,Graham, S.C.,Read, R.J.,Deane, J.E. (deposition date: 2013-10-21, release date: 2013-12-11, Last modification date: 2024-10-23) |
| Primary citation | Hill, C.H.,Graham, S.C.,Read, R.J.,Deane, J.E. Structural Snapshots Illustrate the Catalytic Cycle of Beta-Galactocerebrosidase, the Defective Enzyme in Krabbe Disease Proc.Natl.Acad.Sci.USA, 110:20479-, 2013 Cited by PubMed Abstract: 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 β-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. PubMed: 24297913DOI: 10.1073/PNAS.1311990110 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.09 Å) |
Structure validation
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