Crystal structure of activin receptor type IIB kinase domain.

Activin receptor type IIB (ActRIIB) belongs to a type II transforming growth factor-β (TGF-β) serine/threonine kinase receptor family which is integral to the activin and myostatin signaling pathway. Actvin and myostatin bind to activin type II receptors (ActRIIA and ActRIIB), and the glycine-serine-rich domains of type I receptors are phosphorylated by type II receptors. Activin enhances follicle-stimulating hormone biosynthesis and secretion and is involved in apoptosis, fibrosis, inflammation, and neurogenesis. Because of its essential role, activin is regarded as a novel drug target. Myostatin, also referred as growth and differentiation factor 8 (GDF-8), modulates skeletal muscle growth and has been a therapeutic target for disease conditions such as muscular dystrophy, sarcopenia, cashexia, and diabetes mellitus. The AcRIIB kinase domain from human represents a distinct type II receptor serine/threonine kinase subfamily identifiable in part by common features of Thr265 as a gatekeeper residue and back pocket supported by Phe247. The human ActRII kinase domain structure provides a basis for a more integrated understanding of substrate recognition and catalysis and will also be of help for developing chemical inhibitors.

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