7BUM

mcGAS bound with pGpA

7BUM の概要

• エントリーDOI: 10.2210/pdb7bum/pdb
• 関連するPDBエントリー: 7BUJ
• 分子名称: Cyclic GMP-AMP synthase, ZINC ION, ADENOSINE MONOPHOSPHATE, ... (5 entities in total)
• 機能のキーワード: cgas, activator, inverted-orientation, metal-ion binding protein, immune system
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 118151.43

構造登録者

Wang, B.,Su, X.D. (登録日: 2020-04-07, 公開日: 2020-09-02, 最終更新日: 2024-05-29)

主引用文献

Zhao, Z.,Ma, Z.,Wang, B.,Guan, Y.,Su, X.D.,Jiang, Z.
Mn2+Directly Activates cGAS and Structural Analysis Suggests Mn2+Induces a Noncanonical Catalytic Synthesis of 2'3'-cGAMP.
Cell Rep, 32:108053-108053, 2020

PubMed Abstract: DNA binding allosterically activates the cytosolic DNA sensor cGAS (cyclic GMP-AMP [cGAMP] synthase) to synthesize 2'3'-cGAMP, using Mg as the metal cofactor that catalyzes two nucleotidyl-transferring reactions. We previously found that Mn potentiates cGAS activation, but the underlying mechanism remains unclear. Here, we report that Mn directly activates cGAS. Structural analysis reveals that Mn-activated cGAS undergoes globally similar conformational changes to DNA-activated cGAS but forms a unique η1 helix to widen the catalytic pocket, allowing substrate entry and cGAMP synthesis. Strikingly, in Mn-activated cGAS, the linear intermediates pppGpG and pGpA take an inverted orientation in the active pocket, suggesting a noncanonical but accelerated cGAMP cyclization without substrate flip-over. Moreover, unlike the octahedral coordination around Mg, the two catalytic Mn are coordinated by triphosphate moiety of the inverted substrate, independent of the catalytic triad residues. Our findings thus uncover Mn as a cGAS activator that initiates noncanonical 2'3'-cGAMP synthesis.

PubMed: 32814054
DOI: 10.1016/j.celrep.2020.108053

実験手法

X-RAY DIFFRACTION (3.047 Å)