5G45

Ligand complex of RORg LBD

5G45 の概要

• エントリーDOI: 10.2210/pdb5g45/pdb
• 関連するPDBエントリー: 5G42 5G43 5G44 5G46
• 分子名称: NUCLEAR RECEPTOR ROR-GAMMA, RORG, 8-AMINO-3-QUINOLINOL, ... (6 entities in total)
• 機能のキーワード: dna binding protein, rorg ligand, fragment screen, structure-based design, simultaneous binding
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• 細胞内の位置: Nucleus : P51449
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 32388.16

構造登録者

Xue, Y.,Guo, H.,Hillertz, P. (登録日: 2016-05-04, 公開日: 2016-08-03, 最終更新日: 2024-05-08)

主引用文献

Xue, Y.,Guo, H.,Hillertz, P.
Fragment Screening of Rorgammat Using Cocktail Crystallography: Identification of Simultaneous Binding of Multiple Fragments.
Chemmedchem, 11:1881-, 2016

PubMed Abstract: The retinoic-acid-related orphan receptor γ t (RORγt), as a master regulator of Th17 cell pathology, has become an attractive target for small-molecule drug discovery for the treatment of Th17-cell-related autoimmune diseases. A crystallographic fragment screening was carried out for RORγt using the ligand binding domain. An overall hit rate of 5.5 % was obtained by screening 384 compounds in 96 cocktails. Five distinct hotspots were identified, and four regions of anchoring polar interactions were observed. In addition, significant induced fit was found for the binding of several fragments. Strikingly, a simultaneous binding of three fragments was revealed which presents interesting features including π-π stacking, multiple hydrogen bonds to the protein, and significant induced fit. Overall, the results offer a complete mapping of the ligand binding pocket and provide valuable inspiration in structure-based design for RORγt lead generation and optimization. The crystallographic screening also resulted in fragment hits that bind at the surface away from the ligand binding pocket. This surface site is near the plausible dimer interface by analogy with other nuclear receptor systems, which can provide initial hints to explore alternative ways to modulate RORγt through protein-protein interactions.

PubMed: 27432277
DOI: 10.1002/CMDC.201600242

実験手法

X-RAY DIFFRACTION (2.07 Å)