The catalytic mechanism of cyclic GMP-AMP synthase (cGAS) and implications for innate immunity and inhibition
Related Experiment Video
Updated: Feb 22, 2026

Establishment of a High-throughput Setup for Screening Small Molecules That Modulate c-di-GMP Signaling in Pseudomonas aeruginosa
Published on: June 30, 2016
Justin Hall1, Erik C Ralph1, Suman Shanker1
1Worldwide Medicinal Chemistry, Pfizer, Eastern Point Road, Groton, Connecticut, 06340.
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.
More Related Videos
Related Concept Videos
GPCRs Regulate Adenylyl Cylase Activity
cAMP-dependent Protein Kinase Pathways
Intracellular Signaling Cascades
Activation and Inactivation of G Proteins
Global Regulatory Systems
Calmodulin-dependent Signaling
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...

