3AFR

Crystal Structure of VDR-LBD/22S-Butyl-1a,24R-dihydroxyvitamin D3 complex

3AFR の概要

• エントリーDOI: 10.2210/pdb3afr/pdb
• 関連するPDBエントリー: 2ZXM 2ZXN
• 分子名称: Vitamin D3 receptor, 13-meric peptide from Mediator of RNA polymerase II transcription subunit 1, (1R,3S,5Z)-5-[(2E)-2-{(1R,3aS,7aR)-1-[(1R,2S,4R)-2-butyl-4-hydroxy-1,5-dimethylhexyl]-7a-methyloctahydro-4H-inden-4-yli dene}ethylidene]-4-methylidenecyclohexane-1,3-diol, ... (4 entities in total)
• 機能のキーワード: vitamin d receptor, nuclear receptor, agonist, antagonist, vitamin d derivative, dna-binding, nucleus, receptor, transcription, transcription regulation, transcription-transcription regulator complex, transcription/transcription regulator
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• 細胞内の位置: Nucleus: P13053 A1L0Z0
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 32638.68

構造登録者

Inaba, Y.,Nakabayashi, M.,Itoh, T.,Ikura, T.,Ito, N.,Yamamoto, K. (登録日: 2010-03-10, 公開日: 2010-03-31, 最終更新日: 2023-11-01)

主引用文献

Inaba, Y.,Nakabayashi, M.,Itoh, T.,Yoshimoto, N.,Ikura, T.,Ito, N.,Shimizu, M.,Yamamoto, K.
22S-Butyl-1alpha,24R-dihydroxyvitamin D(3): Recovery of vitamin D receptor agonistic activity
J.Steroid Biochem.Mol.Biol., 121:146-150, 2010

PubMed Abstract: We recently reported that 22S-butyl-1alpha,24R-dihydroxyvitamin D(3)3 recovers the agonistic activity for vitamin D receptor (VDR), although its 25,26,27-trinor analog 2 is a potent VDR antagonist. To investigate the structural features involved in the recovery of agonism, we crystallized the ternary complex of VDR-ligand-binding domain, ligand 3 and coactivator peptide, and conducted X-ray crystallographic analysis of the complex. Compared with the complex with 2, the complex with 3 recovered the following structural features: a pincer-type hydrogen bond between the 24-hydroxyl group and VDR, the conformation of Leu305, the positioning of His301 and His393, the stability of the complex, and intimate hydrophobic interactions between the ligand and helix 12. In addition, we evaluated the potency of both compounds for recruiting RXR and coactivator. The results indicate that the complex with 3 generates a suitable surface for coactivator recruitment. These studies suggest that the action of 2 as an antagonist is caused by the generation of a surface not suitable for coactivator recruitment due to the lack of hydrophobic interactions with helix 12 as well as insufficient hydrogen bond formation between the 24-hydroxyl group and VDR. We concluded that the action of 3 as an agonist is based on the elimination of these structural defects in the complex with 2.

PubMed: 20211257
DOI: 10.1016/j.jsbmb.2010.02.033

実験手法

X-RAY DIFFRACTION (2 Å)