title: Crystal structures of rat vitamin D receptor bound to adamantyl vitamin D analogs: structural basis for vitamin D receptor antagonism and partial agonism.
abstract: The X-ray crystal structures of the rat VDR ligand-binding domain complexed with 19-norvitamin D compounds that contain an adamantyl substituent at the side-chain terminus, 2a (ADTT), 2b (ADNY), and 2c (ADMI4) and a coactivator peptide derived from DRIP205 are reported. These compounds show a series of partial agonistic (10-75% efficacy)/antagonistic activities. All of these complexed receptors are crystallized in the canonical active conformation, regardless of their activity profiles. The bulky adamantyl side chain does not crowd helix 12 but protrudes into the gap formed by helix 11, loop 11-12, helix 3, and loop 6-7, thereby widening the ligand binding pocket. We suggest that these structural changes destabilize the active protein conformation and reduce its contribution to equilibrium among the active and inactive conformations. The coactivator peptide traps the minor active conformation, and the equilibrium shifts to the active conformation. As a result, these ligands show partial agonistic activities.
authors: School of Biomedical Science and Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062.
authors: Makoto
authors: M
authors: Nakabayashi
authors: Sachiko
authors: S
authors: Yamada
authors: Nobuko
authors: N
authors: Yoshimoto
authors: Takashi
authors: T
authors: Tanaka
authors: Miharu
authors: M
authors: Igarashi
authors: Teikichi
authors: T
authors: Ikura
authors: Nobutoshi
authors: N
authors: Ito
authors: Makoto
authors: M
authors: Makishima
authors: Hiroaki
authors: H
authors: Tokiwa
authors: Hector F
authors: HF
authors: DeLuca
authors: Masato
authors: M
authors: Shimizu
mesh_terms: D000218:Adamantane; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D056913:Mediator Complex Subunit 1; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D018167:Receptors, Calcitriol / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry; D014807:Vitamin D / Q000031:analogs & derivatives*
chemical_list: C538857:Med1 protein, rat; D056913:Mediator Complex Subunit 1; D018167:Receptors, Calcitriol; D014157:Transcription Factors; D014807:Vitamin D; D000218:Adamantane