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The catalytic mechanism of cyclic GMP-AMP synthase (cGAS) and implications for innate immunity and inhibition.
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.
Afiliación
  • Hall J; Worldwide Medicinal Chemistry, Pfizer, Eastern Point Road, Groton, Connecticut, 06340.
  • Ralph EC; Worldwide Medicinal Chemistry, Pfizer, Eastern Point Road, Groton, Connecticut, 06340.
  • Shanker S; Worldwide Medicinal Chemistry, Pfizer, Eastern Point Road, Groton, Connecticut, 06340.
  • Wang H; Worldwide Medicinal Chemistry, Pfizer, Eastern Point Road, Groton, Connecticut, 06340.
  • Byrnes LJ; Worldwide Medicinal Chemistry, Pfizer, Eastern Point Road, Groton, Connecticut, 06340.
  • Horst R; Worldwide Medicinal Chemistry, Pfizer, Eastern Point Road, Groton, Connecticut, 06340.
  • Wong J; Hit Discovery and Lead Profiling, Pfizer Centers for Therapeutic Innovation (CTI), Pfizer, Eastern Point Road, Groton, Connecticut, 06340.
  • Brault A; Hit Discovery and Lead Profiling, Pfizer Centers for Therapeutic Innovation (CTI), Pfizer, Eastern Point Road, Groton, Connecticut, 06340.
  • Dumlao D; Hit Discovery and Lead Profiling, Pfizer Centers for Therapeutic Innovation (CTI), Pfizer, Eastern Point Road, Groton, Connecticut, 06340.
  • Smith JF; Hit Discovery and Lead Profiling, Pfizer Centers for Therapeutic Innovation (CTI), Pfizer, Eastern Point Road, Groton, Connecticut, 06340.
  • Dakin LA; Worldwide Medicinal Chemistry, Pfizer, 610 Main St, Cambridge, Massachusetts, 02139.
  • Schmitt DC; Worldwide Medicinal Chemistry, Pfizer, Eastern Point Road, Groton, Connecticut, 06340.
  • Trujillo J; Worldwide Medicinal Chemistry, Pfizer, Eastern Point Road, Groton, Connecticut, 06340.
  • Vincent F; Hit Discovery and Lead Profiling, Pfizer Centers for Therapeutic Innovation (CTI), Pfizer, Eastern Point Road, Groton, Connecticut, 06340.
  • Griffor M; Worldwide Medicinal Chemistry, Pfizer, Eastern Point Road, Groton, Connecticut, 06340.
  • Aulabaugh AE; Worldwide Medicinal Chemistry, Pfizer, Eastern Point Road, Groton, Connecticut, 06340.
Protein Sci ; 26(12): 2367-2380, 2017 Dec.
Article en En | MEDLINE | ID: mdl-28940468
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Nucleótidos Cíclicos / Nucleotidiltransferasas Límite: Humans Idioma: En Revista: Protein Sci Asunto de la revista: BIOQUIMICA Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Nucleótidos Cíclicos / Nucleotidiltransferasas Límite: Humans Idioma: En Revista: Protein Sci Asunto de la revista: BIOQUIMICA Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos