Bone morphogenetic protein (BMP) receptor kinases are tightly regulated to 
control development and tissue homeostasis. Mutant receptor kinase domains 
escape regulation leading to severely degenerative diseases and represent an 
important therapeutic target. Fibrodysplasia ossificans progressiva (FOP) is a 
rare but devastating disorder of extraskeletal bone formation. FOP-associated 
mutations in the BMP receptor ALK2 reduce binding of the inhibitor FKBP12 and 
promote leaky signaling in the absence of ligand. To establish structural 
mechanisms of receptor regulation and to address the effects of FOP mutation, we 
determined the crystal structure of the cytoplasmic domain of ALK2 in complex 
with the inhibitors FKBP12 and dorsomorphin. FOP mutations break critical 
interactions that stabilize the inactive state of the kinase, thereby 
facilitating structural rearrangements that diminish FKBP12 binding and promote 
the correct positioning of the glycine-serine-rich loop and αC helix for kinase 
activation. The balance of these effects accounts for the comparable activity of 
R206H and L196P. Kinase activation in the clinically benign mutant L196P is far 
weaker than R206H but yields equivalent signals due to the stronger interaction 
of FKBP12 with R206H. The presented ALK2 structure offers a valuable template 
for the further design of specific inhibitors of BMP signaling.