Figure 2. Ligand architecture exemplified by BMP-9.

A. The butterfly-like structure of mature dimeric BMP-9 is shown. For clarity, each protomer in the mature, dimeric BMP-9 is colored in a different shade of blue. B. The secondary structure of a ligand protomer is frequently described as a left hand. Structural features have been given names that match the left-hand analogy, including knuckle and palm regions (grey highlight), as well as the wrist helix, prehelix loop, thumb, and fingers (blue highlight). C. Mature dimeric BMP-9 is shown rotated by 90 degrees relative to A with a schematic representation of the type I receptor (grey line) and type II receptor (orange line) binding site located, respectively, near the palm and knuckle regions. D. Surface model showing the BMP-9-ALK1-ActRIIB complex. The orientation is the same as C. The palm region in BMP-9 interacts with the type I receptor (ALK1, grey), the knuckle epitope interacts with the type II receptor (ActRIIB, orange). Images were generated using models of BMP-9 (1ZKZ, ¹⁵³) and BMP-9 in complex with receptor ectodomains (ECD) (BMP-9/ALK1-ECD/ActRIIB-ECD, 4FAO, ¹⁸⁴). Figures were generated using PyMOL (The PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC.)E-G. Schematic representation of the three proposed modes of ligand-receptor assembly (inspired by ^{17, 18}). The figure illustrates important differences in the contact surface between ligands (monomers, blue and light blue), the type I receptors (grey), and type II receptors (orange) for the three paradigms of ligand-receptor assembly. White stars indicate high-affinity binding surfaces between ligand and receptor. E. BMPs bind receptors via a lock-and-key mechanism where the shapes of the binding interfaces in receptors and ligands fit well. The BMPs bind the type II receptors via the knuckle epitope, whereas binding to the type I receptors happens at the concave dimer interface of the ligand and is largely dependent on the ligand pre-helix loop. F. In contrast to BMPs, activins bind type II receptors with high affinity but still position the type II receptors like BMPs at the ligand knuckle epitope. Also, in this case, the type I receptor binds at the concave dimer interface of the ligand. G. TGF-β utilizes a cooperative mode of ligand-receptor assembly, whereby the type II receptor is bound at the ligand fingertip, enabling binding of the type I receptor, ALK5.