Crystal structures of rat vitamin D receptor bound to adamantyl vitamin D analogs

Structural basis for vitamin D receptor antagonism and partial agonism

Makoto Nakabayashi, Sachiko Yamada, Nobuko Yoshimoto, Takashi Tanaka, Miharu Igarashi, Teikichi Ikura, Nobutoshi Ito, Makoto Makishima, Hiroaki Tokiwa, Hector F. DeLuca, Masato Shimizu

Research output: Contribution to journalArticle

56 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5320-5329
Number of pages10
JournalJournal of Medicinal Chemistry
Volume51
Issue number17
DOIs
Publication statusPublished - Sep 11 2008
Externally publishedYes

Fingerprint

Calcitriol Receptors
Vitamin D
Conformations
Rats
Crystal structure
Ligands
Mediator Complex Subunit 1
Peptides
Protein Conformation
X-Rays
X rays
Proteins

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Crystal structures of rat vitamin D receptor bound to adamantyl vitamin D analogs : Structural basis for vitamin D receptor antagonism and partial agonism. / Nakabayashi, Makoto; Yamada, Sachiko; Yoshimoto, Nobuko; Tanaka, Takashi; Igarashi, Miharu; Ikura, Teikichi; Ito, Nobutoshi; Makishima, Makoto; Tokiwa, Hiroaki; DeLuca, Hector F.; Shimizu, Masato.

In: Journal of Medicinal Chemistry, Vol. 51, No. 17, 11.09.2008, p. 5320-5329.

Research output: Contribution to journalArticle

Nakabayashi, M, Yamada, S, Yoshimoto, N, Tanaka, T, Igarashi, M, Ikura, T, Ito, N, Makishima, M, Tokiwa, H, DeLuca, HF & Shimizu, M 2008, 'Crystal structures of rat vitamin D receptor bound to adamantyl vitamin D analogs: Structural basis for vitamin D receptor antagonism and partial agonism', Journal of Medicinal Chemistry, vol. 51, no. 17, pp. 5320-5329. https://doi.org/10.1021/jm8004477
Nakabayashi, Makoto ; Yamada, Sachiko ; Yoshimoto, Nobuko ; Tanaka, Takashi ; Igarashi, Miharu ; Ikura, Teikichi ; Ito, Nobutoshi ; Makishima, Makoto ; Tokiwa, Hiroaki ; DeLuca, Hector F. ; Shimizu, Masato. / Crystal structures of rat vitamin D receptor bound to adamantyl vitamin D analogs : Structural basis for vitamin D receptor antagonism and partial agonism. In: Journal of Medicinal Chemistry. 2008 ; Vol. 51, No. 17. pp. 5320-5329.
@article{e201f32b9534401dbf085359693d75d3,
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.",
author = "Makoto Nakabayashi and Sachiko Yamada and Nobuko Yoshimoto and Takashi Tanaka and Miharu Igarashi and Teikichi Ikura and Nobutoshi Ito and Makoto Makishima and Hiroaki Tokiwa and DeLuca, {Hector F.} and Masato Shimizu",
year = "2008",
month = "9",
day = "11",
doi = "10.1021/jm8004477",
language = "English",
volume = "51",
pages = "5320--5329",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "17",

}

TY - JOUR

T1 - Crystal structures of rat vitamin D receptor bound to adamantyl vitamin D analogs

T2 - Structural basis for vitamin D receptor antagonism and partial agonism

AU - Nakabayashi, Makoto

AU - Yamada, Sachiko

AU - Yoshimoto, Nobuko

AU - Tanaka, Takashi

AU - Igarashi, Miharu

AU - Ikura, Teikichi

AU - Ito, Nobutoshi

AU - Makishima, Makoto

AU - Tokiwa, Hiroaki

AU - DeLuca, Hector F.

AU - Shimizu, Masato

PY - 2008/9/11

Y1 - 2008/9/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=51849126928&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=51849126928&partnerID=8YFLogxK

U2 - 10.1021/jm8004477

DO - 10.1021/jm8004477

M3 - Article

VL - 51

SP - 5320

EP - 5329

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 17

ER -