8A2I

human STING in complex with 2'-3'-cyclic-GMP-7-deaza(4-(2-naphthyl)phenyl)-AMP

8A2I の概要

• エントリーDOI: 10.2210/pdb8a2i/pdb
• 関連するPDBエントリー: 8A2H 8A2J 8A2K
• 分子名称: Stimulator of interferon genes protein, 2-azanyl-9-[(1~{R},6~{R},8~{R},9~{R},10~{S},15~{R},17~{R},18~{R})-8-[4-azanyl-5-(4-naphthalen-2-ylphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-3,9,12,18-tetrakis(oxidanyl)-3,12-bis(oxidanylidene)-2,4,7,11,13,16-hexaoxa-3$l^{5},12$l^{5}-diphosphatricyclo[13.2.1.0^{6,10}]octadecan-17-yl]-3~{H}-purin-6-one (3 entities in total)
• 機能のキーワード: complex, sting, cyclic dinucleotide, immune system
• 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: 55070.70

構造登録者

Vavrina, Z.,Brynda, J.,Rezacova, P. (登録日: 2022-06-03, 公開日: 2022-10-12, 最終更新日: 2024-01-31)

主引用文献

Vavrina, Z.,Perlikova, P.,Milisavljevic, N.,Chevrier, F.,Smola, M.,Smith, J.,Dejmek, M.,Havlicek, V.,Budesinsky, M.,Liboska, R.,Vanekova, L.,Brynda, J.,Boura, E.,Rezacova, P.,Hocek, M.,Birkus, G.
Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7-Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists.
J.Med.Chem., 65:14082-14103, 2022

PubMed Abstract: Cyclic dinucleotides (CDNs) are second messengers that activate stimulator of interferon genes (STING). The cGAS-STING pathway plays a promising role in cancer immunotherapy. Here, we describe the synthesis of CDNs containing 7-substituted 7-deazapurine moiety. We used mouse cyclic GMP-AMP synthase and bacterial dinucleotide synthases for the enzymatic synthesis of CDNs. Alternatively, 7-(het)aryl 7-deazapurine CDNs were prepared by Suzuki-Miyaura cross-couplings. New CDNs were tested in biochemical and cell-based assays for their affinity to human STING. Eight CDNs showed better activity than 2'3'-GAMP, the natural ligand of STING. The effect on cytokine and chemokine induction was also evaluated. The best activities were observed for CDNs bearing large aromatic substituents that point above the CDN molecule. We solved four X-ray structures of complexes of new CDNs with human STING. We observed π-π stacking interactions between the aromatic substituents and Tyr240 that are involved in the stabilization of CDN-STING complexes.

PubMed: 36201304
DOI: 10.1021/acs.jmedchem.2c01305

実験手法

X-RAY DIFFRACTION (2.16 Å)