Structure of the Human cGAS-DNA Complex Reveals Enhanced Control of Immune Surveillance

Cell. 2018 Jul 12;174(2):300-311.e11. doi: 10.1016/j.cell.2018.06.026.


Cyclic GMP-AMP synthase (cGAS) recognition of cytosolic DNA is critical for immune responses to pathogen replication, cellular stress, and cancer. Existing structures of the mouse cGAS-DNA complex provide a model for enzyme activation but do not explain why human cGAS exhibits severely reduced levels of cyclic GMP-AMP (cGAMP) synthesis compared to other mammals. Here, we discover that enhanced DNA-length specificity restrains human cGAS activation. Using reconstitution of cGAMP signaling in bacteria, we mapped the determinant of human cGAS regulation to two amino acid substitutions in the DNA-binding surface. Human-specific substitutions are necessary and sufficient to direct preferential detection of long DNA. Crystal structures reveal why removal of human substitutions relaxes DNA-length specificity and explain how human-specific DNA interactions favor cGAS oligomerization. These results define how DNA-sensing in humans adapted for enhanced specificity and provide a model of the active human cGAS-DNA complex to enable structure-guided design of cGAS therapeutics.

Keywords: STING; cGAS; innate immunity; structural biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Benzofurans / chemistry
  • Benzofurans / metabolism
  • Binding Sites
  • Catalytic Domain
  • Chemotaxis / drug effects
  • DNA / chemistry
  • DNA / metabolism*
  • Humans
  • Immunologic Surveillance / physiology*
  • Mice
  • Molecular Docking Simulation
  • Mutagenesis, Site-Directed
  • Nucleotides, Cyclic / metabolism
  • Nucleotides, Cyclic / pharmacology
  • Nucleotidyltransferases / antagonists & inhibitors
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / metabolism*
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / isolation & purification
  • Species Specificity
  • Vibrio cholerae / metabolism
  • Vibrio cholerae / physiology


  • Benzofurans
  • Nucleotides, Cyclic
  • RU.521
  • Recombinant Proteins
  • cyclic guanosine monophosphate-adenosine monophosphate
  • DNA
  • Nucleotidyltransferases
  • cGAS protein, human