title: Butyl pocket formation in the vitamin D receptor strongly affects the agonistic or antagonistic behavior of ligands.
abstract: Previously, we reported that 22S-butyl-25,26,27-trinor-1α,24-dihydroxyvitamin D(3)2 represents a new class of antagonist for the vitamin D receptor (VDR). The crystal structure of the ligand-binding domain (LBD) of VDR complexed with 2 showed the formation of a butyl pocket to accommodate the 22-butyl group and insufficient interactions between ligand 2 and the C-terminus of VDR. Here, we designed and synthesized new analogues 5a-c and evaluated their biological activities to probe whether agonistic activity is recovered when the analogue restores interactions with the C-terminus of VDR. Analogues 5a-c exhibited full agonistic activity in transactivation. Interestingly, 5c, which bears a 24-diethyl group, completely recovered agonistic activity, although 3c and 4c act as an antagonist and a weak agonist, respectively. The crystal structures of VDR-LBD complexed with 3a, 4a, 5a, and 5c were solved, and the results confirmed that butyl pocket formation in VDR strongly affects the agonistic or antagonistic behaviors of ligands.
authors.affiliation: Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Nobuko
authors.initials: N
authors.lastname: Yoshimoto
authors.forename: Yuta
authors.initials: Y
authors.lastname: Sakamaki
authors.forename: Minoru
authors.initials: M
authors.lastname: Haeta
authors.forename: Akira
authors.initials: A
authors.lastname: Kato
authors.forename: Yuka
authors.initials: Y
authors.lastname: Inaba
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Itoh
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakabayashi
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Ito
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D019556:COS Cells; D002522:Chlorocebus aethiops; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship
chemical_list: D018167:Receptors, Calcitriol; D002762:Cholecalciferol