7BUJ

mcGAS bound with pppGpG

Summary for 7BUJ

• Entry DOI: 10.2210/pdb7buj/pdb
• Descriptor: Cyclic GMP-AMP synthase, ZINC ION, GUANOSINE-5'-TRIPHOSPHATE, ... (6 entities in total)
• Functional Keywords: mcgas, dna-bingding, activator, inverted-orientation, immune system
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 2
• Total formula weight: 105422.23

Authors

Wang, B.,Su, X.D. (deposition date: 2020-04-07, release date: 2020-09-02, Last modification date: 2023-11-29)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.13 Å)