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The catalytic mechanism of cyclic GMP‐AMP synthase (cGAS) and implications for innate immunity and inhibition
Author(s) -
Hall Justin,
Ralph Erik C.,
Shanker Suman,
Wang Hong,
Byrnes Laura J.,
Horst Reto,
Wong Jimson,
Brault Amy,
Dumlao Darren,
Smith James F.,
Dakin Leslie A.,
Schmitt Daniel C.,
Trujillo John,
Vincent Fabien,
Griffor Matt,
Aulabaugh Ann E.
Publication year - 2017
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1002/pro.3304
Subject(s) - innate immune system , atp synthase , microbiology and biotechnology , nucleotide , chemistry , biology , dna , biochemistry , enzyme , receptor , gene
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.