The Catalytic Mechanism of Cyclic GMP-AMP Synthase (cGAS) and Implications for Innate Immunity and Inhibition

Overview

Journal Protein Sci

Specialty Biochemistry

Date 2017 Sep 24

PMID 28940468

Citations 31

Authors

Justin Hall

Erik C Ralph

Suman Shanker

Hong Wang

Laura J Byrnes

Reto Horst

Jimson Wong

Amy Brault

Darren Dumlao

James F Smith

Leslie A Dakin

Daniel C Schmitt

John Trujillo

Fabien Vincent

Matt Griffor

Ann E Aulabaugh

Affiliations

Soon will be listed here.

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.

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