3FAL

humanRXR alpha & mouse LXR alpha complexed with Retenoic acid and GSK2186

3FAL の概要

• エントリーDOI: 10.2210/pdb3fal/pdb
• 分子名称: Retinoic acid receptor RXR-alpha, Oxysterols receptor LXR-alpha, RETINOIC ACID, ... (5 entities in total)
• 機能のキーワード: nuclear hormone receptor nonsteroidal lxr agonist choloestorol metabolism, dna-binding, host-virus interaction, metal-binding, nucleus, polymorphism, receptor, transcription, transcription regulation, ubl conjugation, zinc, zinc-finger, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Nucleus: P19793; Nucleus (Potential): Q9Z0Y9
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 117065.62

構造登録者

Chao, E.Y.,Caravella, J.A.,Watson, M.A.,Campobasso, N.,Ghisletti, S.,Billin, A.N.,Galardi, C.,Willson, T.M.,Zuercher, W.J.,Collins, J.L. (登録日: 2008-11-17, 公開日: 2009-04-14, 最終更新日: 2023-12-27)

主引用文献

Chao, E.Y.,Caravella, J.A.,Watson, M.A.,Campobasso, N.,Ghisletti, S.,Billin, A.N.,Galardi, C.,Wang, P.,Laffitte, B.A.,Iannone, M.A.,Goodwin, B.J.,Nichols, J.A.,Parks, D.J.,Stewart, E.,Wiethe, R.W.,Williams, S.P.,Smallwood, A.,Pearce, K.H.,Glass, C.K.,Willson, T.M.,Zuercher, W.J.,Collins, J.L.
Structure-guided design of N-phenyl tertiary amines as transrepression-selective liver X receptor modulators with anti-inflammatory activity.
J.Med.Chem., 51:5758-5765, 2008

PubMed Abstract: A cocrystal structure of T1317 (3) bound to hLXRbeta was utilized in the design of a series of substituted N-phenyl tertiary amines. Profiling in binding and functional assays led to the identification of LXR modulator GSK9772 ( 20) as a high-affinity LXRbeta ligand (IC 50 = 30 nM) that shows separation of anti-inflammatory and lipogenic activities in human macrophage and liver cell lines, respectively. A cocrystal structure of the structurally related analog 19 bound to LXRbeta reveals regions within the receptor that can affect receptor modulation through ligand modification. Mechanistic studies demonstrate that 20 is greater than 10-fold selective for LXR-mediated transrepression of proinflammatory gene expression versus transactivation of lipogenic signaling pathways, thus providing an opportunity for the identification of LXR modulators with improved therapeutic indexes.

PubMed: 18800767
DOI: 10.1021/jm800612u

実験手法

X-RAY DIFFRACTION (2.36 Å)