Extended Data Figure 6: α-Klotho interaction with rigid core of FGF23 and a second binding pocket next to the hydrophobic groove in FGFR1c D3.

a, A partial view of the ternary complex. α-Klotho^ecto (cyan/blue solid surface, RBA of KL2 in blue cartoon), FGF23 (orange transparent surface and cartoon), FGFR1c (constant region: solid green surface; alternatively spliced region: solid purple surface). Dashed black circle denotes the perimeter of the interface between proximal end of α-klotho RBA and a second binding pocket (SBP) in FGFR1c D3 next to the hydrophobic groove. Solid black box denotes the perimeter of α-klotho−FGF23^core interface. b, Close-up view of the interface between proximal end of RBA and SBP in D3. The disulfide bridge between Cys572 (N-terminal end of RBA) and Cys621 (α2 helix) at the base of the RBA probably imparts some degree of conformational rigidity to the proximal RBA portion, whereas the conformation of the distal RBA tip is dictated by contacts with FGFR1c D3. c, Close-up view of the α-klotho−FGF23^core interface detailing hydrogen bonding (top) and hydrophobic contacts (bottom). Grey transparent surfaces denote hydrophobic interactions; dashed yellow lines denote hydrogen bonding contacts.