6CT9

Structure of the human cGAS-DNA complex

Summary for 6CT9

• Entry DOI: 10.2210/pdb6ct9/pdb
• Descriptor: Cyclic GMP-AMP synthase, DNA (5'-D(P*CP*GP*TP*CP*TP*TP*CP*GP*GP*CP*AP*AP*T)-3'), DNA (5'-D(*AP*AP*AP*TP*TP*GP*CP*CP*GP*AP*AP*GP*AP*CP*GP*A)-3'), ... (5 entities in total)
• Functional Keywords: cgas, sting, innate immunity, transferase, transferase-dna complex, transferase/dna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 53353.51

Authors

Zhou, W.,Whiteley, A.T.,de Oliveira Mann, C.C.,Morehouse, B.R.,Mekalanos, J.J.,Kranzusch, P.J. (deposition date: 2018-03-22, release date: 2018-07-18, Last modification date: 2023-10-04)

Primary citation

Zhou, W.,Whiteley, A.T.,de Oliveira Mann, C.C.,Morehouse, B.R.,Nowak, R.P.,Fischer, E.S.,Gray, N.S.,Mekalanos, J.J.,Kranzusch, P.J.
Structure of the Human cGAS-DNA Complex Reveals Enhanced Control of Immune Surveillance.
Cell, 174:300-311.e11, 2018

PubMed Abstract: 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.

PubMed: 30007416
DOI: 10.1016/j.cell.2018.06.026

Experimental method

X-RAY DIFFRACTION (2.26 Å)