9WQ3

Structure of 3TM-SAVED Filament bound to 2'3'-cGAMP

Summary for 9WQ3

• Entry DOI: 10.2210/pdb9wq3/pdb
• EMDB information: 66158
• Descriptor: 2-methylthioadenine synthetase, cGAMP (2 entities in total)
• Functional Keywords: saved, immune system
• Biological source: Bacillus thuringiensis
• Total number of polymer chains: 6
• Total formula weight: 255933.43

Authors

Gao, Y.N. (deposition date: 2025-09-10, release date: 2026-04-01, Last modification date: 2026-07-29)

Primary citation

Gao, Y.,Li, Z.,Zhou, Y.,Li, W.,Li, Q.,Wang, J.,Shi, M.,Ye, F.,Zhao, C.,Liu, S.,Jiang, Q.,Zhu, Y.,Sun, F.,Gao, A.,Gao, P.
2'3'-cGAMP-induced membrane shearing promotes broad antiphage immunity.
Cell, 189:3636-3650.e19, 2026

PubMed Abstract: Cyclic-oligonucleotide-based anti-phage signaling system (CBASS), a central prokaryotic antiviral strategy and evolutionary ancestor of the mammalian cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, relies on cyclic-nucleotide-activated effectors to elicit immunity. The most prevalent effectors are transmembrane (TM) proteins, yet their mechanisms remain unknown. Here, we show how a representative three transmembrane (3TM)-SMODS-associated fused to various effector domains (SAVED) effector couples ligand sensing to membrane disruption. Upon binding 2'3'-cyclic GMP-AMP (cGAMP)-synthesized by bacterial cGAS/DncV-like nucleotidyltransferase (CD-NTase) with features resembling mammalian cGAS-3TM-SAVED assembles stepwise from an apo monomer through a transient dimer into extended filaments. Filament assembly employs 2'3'-cGAMP as molecular glue linking SAVED domains and reorients TM helices and amphipathic hairpins into vertically offset arrays. Both arrays bear opposing hydrophobic and hydrophilic faces, thereby driving vertical lipid shearing. This shearing generates a linear pore array that permeabilizes membranes and triggers cell death. These findings uncover the long-missing mechanism of CBASS TM effectors and establish vertical membrane shearing as an unrecognized principle of membrane disruption across domains of life.

PubMed: 41999741
DOI: 10.1016/j.cell.2026.03.043

Experimental method

ELECTRON MICROSCOPY (3.27 Å)