6T13

CRYSTAL STRUCTURE OF GLUCOCEREBROSIDASE IN COMPLEX WITH A PYRROLOPYRAZINE

6T13 の概要

• エントリーDOI: 10.2210/pdb6t13/pdb
• 分子名称: Glucosylceramidase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, SULFATE ION, ... (10 entities in total)
• 機能のキーワード: gcase, glycosidase, cerezyme, hydrolysis, hydrolase, glycosylceramidase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 243175.56

構造登録者

Benz, J.,Ehler, A.,Hug, M.,Huber, S.,Rufer, A.C.,Guba, W.,Jagasia, R.,Hofmann, E.C.,Rodriguez Sarmiento, R.M. (登録日: 2019-10-03, 公開日: 2020-12-23, 最終更新日: 2024-11-20)

主引用文献

Benz, J.,Rufer, A.C.,Huber, S.,Ehler, A.,Hug, M.,Topp, A.,Guba, W.,Hofmann, E.C.,Jagasia, R.,Rodriguez Sarmiento, R.M.
Novel beta-Glucocerebrosidase Activators That Bind to a New Pocket at a Dimer Interface and Induce Dimerization.
Angew.Chem.Int.Ed.Engl., 60:5436-5442, 2021

PubMed Abstract: Genetic, preclinical and clinical data link Parkinson's disease and Gaucher's disease and provide a rational entry point to disease modification therapy via enhancement of β-Glucocerebrosidase (GCase) activity. We discovered a new class of pyrrolo[2,3-b]pyrazine activators effecting both Vmax and Km. They bind to human GCase and increase substrate metabolism in the lysosome in a cellular assay. We obtained the first crystal structure for an activator and identified a novel non-inhibitory binding mode at the interface of a dimer, rationalizing the observed structure-activity relationship (SAR). The compound binds GCase inducing formation of a dimeric state at both endoplasmic reticulum (ER) and lysosomal pHs, as confirmed by analytical ultracentrifugation. Importantly, the pyrrolo[2,3-b]pyrazines have central nervous system (CNS) drug-like properties. Our findings are important for future drug discovery efforts in the field of GCase activation and provide a deeper mechanistic understanding of the requirements for enzymatic activation, pointing to the relevance of dimerization.

PubMed: 33238058
DOI: 10.1002/anie.202013890

実験手法

X-RAY DIFFRACTION (1.85 Å)