Adaptability of the Vitamin D nuclear receptor to the synthetic ligand Gemini: remodelling the LBP with one side chain rotation.
The crystal structure of the ligand binding domain (LBD) of the wild-type Vitamin D receptor (VDR) of zebrafish bound to Gemini, a synthetic agonist ligand with two identical side chains branching at carbon 20 reveals a ligand-dependent structural rearrangement of the ligand binding pocket (LBP). The rotation of a Leu side chain opens the access to a channel that can accommodate the second side chain of the ligand. The 25% increase of the LBP's volume does not alter the essential agonist features of VDR. The possibility to adapt the LBP to novel ligands with different chemistry and/or structure opens new perspectives in the design of more specifically targeted ligands.
Ciesielski
Fabrice
F
Département de Biologie et de Génomique Structurales, IGBMC, CNRS/INSERM Université Louis Pasteur, Parc d'innovation BP10142, 67404 Illkirch Cedex, France.
Rochel
Natacha
N
Moras
Dino
D
D000220:Adaptation, Biological; D000818:Animals; D001665:Binding Sites; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D018167:Receptors, Calcitriol / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish
C411462:1,25-dihydroxy-21-(3-hydroxy-3-methylbutyl)vitamin D(3); D008024:Ligands; D018167:Receptors, Calcitriol; D002117:Calcitriol