8T5K

Crystal structure of STING CTD in complex with BDW-OH

8T5K の概要

• エントリーDOI: 10.2210/pdb8t5k/pdb
• 分子名称: Stimulator of interferon genes protein, {[(4S)-8,9-dimethylthieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidin-3-yl]sulfanyl}acetic acid (3 entities in total)
• 機能のキーワード: mediator of irf3 activation, stimulator of interferon genes protein, antiviral protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 21851.58

構造登録者

Li, Y.,Li, P.,Sun, D. (登録日: 2023-06-13, 公開日: 2023-07-12, 最終更新日: 2023-10-25)

主引用文献

Tang, Z.,Zhao, J.,Li, Y.,Tomer, S.,Selvaraju, M.,Tien, N.,Sun, D.,Johnson, D.K.,Zhen, A.,Li, P.,Wang, J.
Structural and Biological Evaluations of a Non-Nucleoside STING Agonist Specific for Human STING A230 Variants.
Biorxiv, 2023

PubMed Abstract: Previously we identified a non-nucleotide tricyclic agonist BDW568 that activates human STING (stimulator of interferon genes) gene variant containing A230 in a human monocyte cell line (THP-1). STING alleles, including HAQ and AQ, are less common STING variants in human population. To further characterize the mechanism of BDW568, we obtained the crystal structure of the C-terminal domain of STING complexed with BDW-OH (active metabolite of BDW568) at 1.95 Å resolution and found the planar tricyclic structure in BDW-OH dimerizes in the STING binding pocket and mimics the two nucleobases of the endogenous STING ligand 2',3'-cGAMP. This binding mode also resembles a known synthetic ligand of human STING, MSA-2, but not another tricyclic mouse STING agonist DMXAA. Structure-activity-relationship (SAR) studies revealed that all three heterocycles in BDW568 and the S-acetate side chain are critical for retaining the compound's activity. BDW568 could robustly activate the STING pathway in human primary peripheral blood mononuclear cells (PBMCs) with STING genotype from healthy individuals. We also observed BDW568 could robustly activate type I interferon signaling in purified human primary macrophages that were transduced with lentivirus expressing STING, suggesting its potential use to selectively activate genetically engineered macrophages in macrophage-based approaches, such as chimeric antigen receptor (CAR)-macrophage immunotherapies.

PubMed: 37425806
DOI: 10.1101/2023.07.02.547363

実験手法

X-RAY DIFFRACTION (1.95 Å)