4CCC

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

4CCC の概要

• エントリーDOI: 10.2210/pdb4ccc/pdb
• 関連するPDBエントリー: 4CCD 4CCE
• 分子名称: 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)
• 機能のキーワード: hydrolase, krabbe disease, glycosyl hydrolase, 4-nitrophenyl-beta-d-galactopyranoside, lysosomal storage disease, enzyme- substrate complex
• 由来する生物種: MUS MUSCULUS (HOUSE MOUSE)
• 細胞内の位置: Lysosome (By similarity): P54818
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 76432.49

構造登録者

Hill, C.H.,Graham, S.C.,Read, R.J.,Deane, J.E. (登録日: 2013-10-21, 公開日: 2013-12-11, 最終更新日: 2024-10-23)

主引用文献

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

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: 24297913
DOI: 10.1073/PNAS.1311990110

実験手法

X-RAY DIFFRACTION (2.09 Å)