5VDW

Human cyclic GMP-AMP synthase (cGAS) in complex with Compound F1

5VDW の概要

• エントリーDOI: 10.2210/pdb5vdw/pdb
• 関連するPDBエントリー: 5VDO 5VDP 5VDQ 5VDR 5VDS 5VDT 5VDU 5VDV
• 分子名称: Cyclic GMP-AMP synthase, ZINC ION, [2-(1,3-thiazol-4-yl)-1H-benzimidazol-1-yl]acetic acid, ... (4 entities in total)
• 機能のキーワード: transferase, sting, cgamp
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm, cytosol . Note=(Microbial infection) Upon infection with virulent M: Q8N884
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 85721.59

構造登録者

Byrnes, L.J.,Hall, J.D. (登録日: 2017-04-03, 公開日: 2017-09-27, 最終更新日: 2023-10-04)

主引用文献

Hall, J.,Ralph, E.C.,Shanker, S.,Wang, H.,Byrnes, L.J.,Horst, R.,Wong, J.,Brault, A.,Dumlao, D.,Smith, J.F.,Dakin, L.A.,Schmitt, D.C.,Trujillo, J.,Vincent, F.,Griffor, M.,Aulabaugh, A.E.
The catalytic mechanism of cyclic GMP-AMP synthase (cGAS) and implications for innate immunity and inhibition.
Protein Sci., 26:2367-2380, 2017

PubMed Abstract: Cyclic GMP-AMP synthase (cGAS) is activated by ds-DNA binding to produce the secondary messenger 2',3'-cGAMP. cGAS is an important control point in the innate immune response; dysregulation of the cGAS pathway is linked to autoimmune diseases while targeted stimulation may be of benefit in immunoncology. We report here the structure of cGAS with dinucleotides and small molecule inhibitors, and kinetic studies of the cGAS mechanism. Our structural work supports the understanding of how ds-DNA activates cGAS, suggesting a site for small molecule binders that may cause cGAS activation at physiological ATP concentrations, and an apparent hotspot for inhibitor binding. Mechanistic studies of cGAS provide the first kinetic constants for 2',3'-cGAMP formation, and interestingly, describe a catalytic mechanism where 2',3'-cGAMP may be a minor product of cGAS compared with linear nucleotides.

PubMed: 28940468
DOI: 10.1002/pro.3304

実験手法

X-RAY DIFFRACTION (2.711 Å)