Sie können Bookmarks mittels Listen verwalten, loggen Sie sich dafür bitte in Ihr SLUB Benutzerkonto ein.
Medientyp:
E-Artikel
Titel:
Novel β‐Glucocerebrosidase Activators That Bind to a New Pocket at a Dimer Interface and Induce Dimerization
Beteiligte:
Benz, Joerg;
Rufer, Arne C.;
Huber, Sylwia;
Ehler, Andreas;
Hug, Melanie;
Topp, Andreas;
Guba, Wolfgang;
Hofmann, Eva Carolina;
Jagasia, Ravi;
Rodríguez Sarmiento, Rosa María
Erschienen:
Wiley, 2021
Erschienen in:Angewandte Chemie International Edition
Sprache:
Englisch
DOI:
10.1002/anie.202013890
ISSN:
1433-7851;
1521-3773
Entstehung:
Anmerkungen:
Beschreibung:
<jats:title>Abstract</jats:title><jats:p>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.</jats:p>