4O68

Structure of human cyclic GMP-AMP synthase (cGAS)

Summary for 4O68

• Entry DOI: 10.2210/pdb4o68/pdb
• Related: 4O67 4O69 4O6A
• Descriptor: Cyclic GMP-AMP synthase, ZINC ION (3 entities in total)
• Functional Keywords: immune responses, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytosol: Q8N884
• Total number of polymer chains: 1
• Total formula weight: 43916.03

Authors

Zhang, X.,Chen, Z.,Zhang, X.W.,Chen, Z.J. (deposition date: 2013-12-20, release date: 2014-02-05, Last modification date: 2024-02-28)

Primary citation

Zhang, X.,Wu, J.,Du, F.,Xu, H.,Sun, L.,Chen, Z.,Brautigam, C.A.,Zhang, X.,Chen, Z.J.
The Cytosolic DNA Sensor cGAS Forms an Oligomeric Complex with DNA and Undergoes Switch-like Conformational Changes in the Activation Loop.
Cell Rep, 6:421-430, 2014

PubMed Abstract: The presence of DNA in the cytoplasm is a danger signal that triggers immune and inflammatory responses. Cytosolic DNA binds to and activates cyclic GMP-AMP (cGAMP) synthase (cGAS), which produces the second messenger cGAMP. cGAMP binds to the adaptor protein STING and activates a signaling cascade that leads to the production of type I interferons and other cytokines. Here, we report the crystal structures of human cGAS in its apo form, representing its autoinhibited conformation as well as in its cGAMP- and sulfate-bound forms. These structures reveal switch-like conformational changes of an activation loop that result in the rearrangement of the catalytic site. The structure of DNA-bound cGAS reveals a complex composed of dimeric cGAS bound to two molecules of DNA. Functional analyses of cGAS mutants demonstrate that both the protein-protein interface and the two DNA binding surfaces are critical for cGAS activation. These results provide insights into the mechanism of DNA sensing by cGAS.

PubMed: 24462292
DOI: 10.1016/j.celrep.2014.01.003

Experimental method

X-RAY DIFFRACTION (2.436 Å)