Repulsive guidance molecules lock growth differentiation factor 5 in an inhibitory complex

Significance Repulsive guidance molecules (RGMs) are cell surface proteins that control processes ranging from brain development to iron metabolism. Dysregulation of RGM function leads to severe diseases. RGMs can bind to the cell guidance receptor Neogenin (NEO1) and act as coreceptors for the bone morphogenetic proteins (BMPs). Here, we determined high-resolution structures of all three human RGMs in complex with the BMP ligand growth differentiation factor 5 (GDF5) and the ternary complex of GDF5 with RGM and NEO1. Our structural and functional analyses reveal that RGM competes with the GDF5 receptor. This study shows that RGMs can act as inhibitors of a BMP ligand (GDF5), and not always as activators of BMP signaling, as previously reported.