6MXE

Crystal structure of human STING (G230A, H232R, R293Q) in complex with Compound 18

6MXE の概要

• エントリーDOI: 10.2210/pdb6mxe/pdb
• 分子名称: Stimulator of interferon genes protein, [(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]acetic acid, CALCIUM ION, ... (4 entities in total)
• 機能のキーワード: innate immunity, signaling, open conformation, immune system, immune system-inhibitor complex, immune system/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 44184.45

構造登録者

Lesburg, C.A.,Siu, T.,Ho, T. (登録日: 2018-10-30, 公開日: 2018-12-19, 最終更新日: 2024-03-13)

主引用文献

Siu, T.,Altman, M.D.,Baltus, G.A.,Childers, M.,Ellis, J.M.,Gunaydin, H.,Hatch, H.,Ho, T.,Jewell, J.,Lacey, B.M.,Lesburg, C.A.,Pan, B.S.,Sauvagnat, B.,Schroeder, G.K.,Xu, S.
Discovery of a Novel cGAMP Competitive Ligand of the Inactive Form of STING.
ACS Med Chem Lett, 10:92-97, 2019

PubMed Abstract: Drugging large protein pockets is a challenge due to the need for higher molecular weight ligands, which generally possess undesirable physicochemical properties. In this communication, we highlight a strategy leveraging small molecule active site dimers to inhibit the large symmetric binding pocket in the STING protein. By taking advantage of the 2:1 binding stoichiometry, maximal buried interaction with STING protein can be achieved while maintaining the ligand physicochemical properties necessary for oral exposure. This mode of binding requires unique considerations for potency optimization including simultaneous optimization of protein-ligand as well as ligand-ligand interactions. Successful implementation of this strategy led to the identification of , which exhibits good oral exposure, slow binding kinetics, and functional inhibition of STING-mediated cytokine release.

PubMed: 30655953
DOI: 10.1021/acsmedchemlett.8b00466

実験手法

X-RAY DIFFRACTION (2.47 Å)