Proposed mechanism of Cerberus inhibition.(A) Structure of BMP9-ALK1-ACTRIIB complex. The disulfide linked BMP9 dimer (center,
orange) simultaneously binds the extracellular domains of the type I Activin receptor-like
kinase ALK1 (light blue) and the type II Activin receptor kinase ACTRIIB (dark blue).
Cerberus prevents binding of Nodal to ALK4, ACTRIIB and Cripto-1. (B) Molecular model of Nodal-receptor interactions based on the BMP9-ALK1-ACTRIIB structure.
The disulfide linked Nodal dimer (center, orange) binds the extracellular domains
of the type I Activin receptor-like kinase ALK4 (light blue) and the type II Activin
receptor kinase ACTRIIB or BMPRII (dark blue), likely using canonical interaction
surfaces (yellow lined circles). (C-D) Model of Cerberus inhibition. Dimeric Cerberus prevents binding of Nodal to both
receptors, possibly by blocking simultaneously the ALK4 interaction surface (light
blue circle) and the ACTRIIB interaction surface (dark blue circle). One Cerberus
molecule could block interaction surfaces within one Nodal protomer (C) or two protomers (D).
