Advances in Vitamin D Receptor Function and Evolution Based on the 3D Structure of the Lamprey Ligand-Binding Domain

1α,25-dihydroxyvitamin
D3 (1,25D3) regulates many
physiological processes in vertebrates by binding to the vitamin D
receptor (VDR). Phylogenetic analysis indicates that jawless fishes
are the most basal vertebrates exhibiting a VDR gene. To elucidate
the mechanism driving VDR activation during evolution, we determined
the crystal structure of the VDR ligand-binding domain (LBD) complex
from the basal vertebratePetromyzon marinus, sea lamprey (lVDR). Comparison of three-dimensional crystal structures
of the lVDR–1,25D3 complex with higher vertebrate
VDR–1,25D3 structures suggests that 1,25D3 binds to lVDR similarly to human VDR, but with unique features for
lVDR around linker regions between H11 and H12 and between H9 and
H10. These structural differences may contribute to the marked species
differences in transcriptional responses. Furthermore, residue co-evolution
analysis of VDR across vertebrates identifies amino acid positions
in H9 and the large insertion domain VDR LBD specific as correlated.