<p><b>A</b>: 3D presentation of the human GDF5 homodimer (PDB 1waq). The topology of the GDF5 monomer comprises two ß-sheets forming the fingers as well as the four-turn α-helix with the preceding pre-helix loop. The mutations are highlighted in pink (GDF5<sup>W414R</sup>), violet (GDF5<sup>R399C</sup>) and orange (GDF5<sup>E491K</sup>). The image of the GDF5 structure was visualized using PyMol (<a href="http://www.pymol.org/" target="_blank">http://www.pymol.org/</a>). <b>B</b>: Protein sequence alignment of human, mouse and chicken GDF5 comprising the seven cysteine residues (bold) of the mature domain. Numbering is referred to the pro-protein sequence. Amino acids predicted to form the NOG binding interface are depicted as framed white boxes and based on the BMP7:NOG complex (PDB 1m4u). Residues predicted to be involved in BMPR1A binding are shown as grey boxes and refer to the BMP2:BMPR1A structure (PDB 1rew). Black boxes mark amino acids that bind to BMPR1B (PDB 3evs). Arrows indicate the mutated sites for GDF5<sup>W414R</sup>, GDF5<sup>R399C</sup> and GDF5<sup>E491K</sup>. Note that GDF5<sup>W414R</sup> and GDF5<sup>E491K</sup> are located within the NOG binding site. Moreover, all three mutations interfere with the BMP type I receptor (BMPR1A and BMPR1B) binding interface.</p
