8SJ8

Structure of binary complex of human cGAS and bound ppp(2'-5')GpG

Summary for 8SJ8

• Entry DOI: 10.2210/pdb8sj8/pdb
• Descriptor: Cyclic GMP-AMP synthase, ZINC ION, [[(2~{R},3~{R},4~{R},5~{R})-5-(2-azanyl-6-oxidanylidene-1~{H}-purin-9-yl)-4-[[(2~{R},3~{S},4~{R},5~{R})-5-(2-azanyl-6-oxidanylidene-1~{H}-purin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl]oxy-3-oxidanyl-oxolan-2-yl]methoxy-oxidanyl-phosphoryl] phosphono hydrogen phosphate, ... (4 entities in total)
• Functional Keywords: immune system, transferase, ligands, intermediate
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 43908.27

Authors

Wu, S.,Sohn, J. (deposition date: 2023-04-17, release date: 2024-04-24, Last modification date: 2024-05-29)

Primary citation

Wu, S.,Gabelli, S.B.,Sohn, J.
The structural basis for 2'-5'/3'-5'-cGAMP synthesis by cGAS.
Nat Commun, 15:4012-4012, 2024

PubMed Abstract: cGAS activates innate immune responses against cytosolic double-stranded DNA. Here, by determining crystal structures of cGAS at various reaction stages, we report a unifying catalytic mechanism. apo-cGAS assumes an array of inactive conformations and binds NTPs nonproductively. Dimerization-coupled double-stranded DNA-binding then affixes the active site into a rigid lock for productive metal•substrate binding. A web-like network of protein•NTP, intra-NTP, and inter-NTP interactions ensures the stepwise synthesis of 2'-5'/3'-5'-linked cGAMP while discriminating against noncognate NTPs and off-pathway intermediates. One divalent metal is sufficient for productive substrate binding, and capturing the second divalent metal is tightly coupled to nucleotide and linkage specificities, a process which manganese is preferred over magnesium by 100-fold. Additionally, we elucidate how mouse cGAS achieves more stringent NTP and linkage specificities than human cGAS. Together, our results reveal that an adaptable, yet precise lock-and-key-like mechanism underpins cGAS catalysis.

PubMed: 38740774
DOI: 10.1038/s41467-024-48365-3

Experimental method

X-RAY DIFFRACTION (2.5 Å)