2ZMJ

Crystal Structure of Rat Vitamin D Receptor Bound to Adamantyl Vitamin D Analogs: Structural Basis for Vitamin D Receptor Antagonism and/or Partial Agonism

2ZMJ の概要

• エントリーDOI: 10.2210/pdb2zmj/pdb
• 関連するPDBエントリー: 2ZMH 2ZMI
• 分子名称: Vitamin D3 receptor, Mediator of RNA polymerase II transcription subunit 1, (1R,3R,7E,17beta)-17-{(1S,2E,5R)-5-hydroxy-1-methyl-6-[(3S,5S,7S)-tricyclo[3.3.1.1~3,7~]dec-1-yl]hex-2-en-1-yl}-2-methylidene-9,10-secoestra-5,7-diene-1,3-diol, ... (4 entities in total)
• 機能のキーワード: nuclear receptor-antagonist complex, dna-binding, metal-binding, nucleus, phosphoprotein, receptor, transcription, transcription regulation, zinc, zinc-finger, activator
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• 細胞内の位置: Nucleus: P13053; Nucleus (By similarity): A1L0Z0
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 32700.75

構造登録者

Nakabayashi, M.,Yamada, S.,Tanaka, T.,Igarashi, M.,Yoshimoto, N.,Ikura, T.,Ito, N.,Makishima, M.,Tokiwa, H.,DeLuca, H.F.,Shimizu, M. (登録日: 2008-04-19, 公開日: 2008-09-02, 最終更新日: 2024-03-13)

主引用文献

Nakabayashi, M.,Yamada, S.,Yoshimoto, N.,Tanaka, T.,Igarashi, M.,Ikura, T.,Ito, N.,Makishima, M.,Tokiwa, H.,DeLuca, H.F.,Shimizu, M.
Crystal structures of rat vitamin d receptor bound to adamantyl vitamin d analogs: structural basis for vitamin d receptor antagonism and partial agonism
J.Med.Chem., 51:5320-5329, 2008

PubMed 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.

PubMed: 18710208
DOI: 10.1021/jm8004477

実験手法

X-RAY DIFFRACTION (2.35 Å)