6T13
CRYSTAL STRUCTURE OF GLUCOCEREBROSIDASE IN COMPLEX WITH A PYRROLOPYRAZINE
Summary for 6T13
| Entry DOI | 10.2210/pdb6t13/pdb |
| Descriptor | Glucosylceramidase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, SULFATE ION, ... (10 entities in total) |
| Functional Keywords | gcase, glycosidase, cerezyme, hydrolysis, hydrolase, glycosylceramidase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 243175.56 |
| Authors | Benz, J.,Ehler, A.,Hug, M.,Huber, S.,Rufer, A.C.,Guba, W.,Jagasia, R.,Hofmann, E.C.,Rodriguez Sarmiento, R.M. (deposition date: 2019-10-03, release date: 2020-12-23, Last modification date: 2024-01-24) |
| Primary citation | 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 Cited by 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: 33238058DOI: 10.1002/anie.202013890 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.85 Å) |
Structure validation
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