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 language | English |
|---|---|
| Pages (from-to) | 5320-5329 |
| Number of pages | 10 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 51 |
| Issue number | 17 |
| DOIs | |
| Publication status | Published - Sep 11 2008 |
| Externally published | Yes |
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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 journal › Article
}
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.
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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 -