9WHU

Structure of Klebsiella pneumoniae trypsin-HamAB bound with DNA, trimer

Summary for 9WHU

• Entry DOI: 10.2210/pdb9whu/pdb
• EMDB information: 65977
• Descriptor: Anti-bacteriophage protein A/HamA C-terminal domain-containing protein, DNA polymerase theta (Helicase domain only), DNA (5'-D(P*AP*AP*AP*AP*AP*AP*A)-3'), ... (4 entities in total)
• Functional Keywords: atpase, helicase, dna binding protein/dna, dna binding protein-dna complex
• Biological source: Klebsiella pneumoniae; More
• Total number of polymer chains: 9
• Total formula weight: 483021.19

Authors

Huang, P.P.,Liu, J.X.,Shen, L.B.,Chen, M.R.,Xiao, Y.B. (deposition date: 2025-08-27, release date: 2026-06-03, Last modification date: 2026-07-29)

Primary citation

Huang, P.,Liu, J.,Guo, L.,Xu, D.,Shen, L.,Yan, P.,Tong, C.,Fei, W.,Cheng, M.,Li, Z.,Lu, M.,Zhang, L.,Wu, N.,Qi, L.W.,Xiao, Y.,Chen, M.
The antiphage mechanism of a widespread trypsin-MBL defense module.
Nat.Chem.Biol., 2026

PubMed Abstract: Protease-mediated activation of immune effectors is an evolutionarily conserved mechanism. This study identifies a widespread trypsin-MBL (metallo-β-lactamase) module as a core effector in diverse antiviral bacterial immune systems, such as Hachiman, AVAST and Argonaute. Focusing on the Hachiman-associated trypsin-MBL system, we show that trypsin•HamAB protease activity is inhibited by ATP, while MBL is an autoinhibited DNase with two insertion loops obstructing its catalytic site. Upon infection, trypsin•HamAB senses foreign DNA and hydrolyzes ATP, activating trypsin-like activity, which specifically cleaves MBL at the insertion loops to release repression. The activated MBL depletes DNA and arrests host cell growth. Cryo-electron microscopy structures of trypsin•HamAB-DNA reveal that DNA binding and ATP hydrolysis trigger HamAB oligomerization and trypsin-like domain release, enabling its activation. Our work elucidates a conserved immune mechanism wherein proteolytic activation of a nuclease enables robust immunity against phage while multilayered controls prevent self-toxicity, expanding the repertoire of immune processes governed by regulatory proteolysis.

PubMed: 42243536
DOI: 10.1038/s41589-026-02252-8

Experimental method

ELECTRON MICROSCOPY (3.5 Å)