9K1S

Crystal structure of human granzyme A in complex with GSDMB-C domain

Summary for 9K1S

• Entry DOI: 10.2210/pdb9k1s/pdb
• Descriptor: Granzyme A, Isoform 4 of Gasdermin-B, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: complex, pyroptosis, protease, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 93745.43

Authors

Zhong, X.,Hou, Y.J.,Ding, J. (deposition date: 2024-10-16, release date: 2026-02-18, Last modification date: 2026-02-25)

Primary citation

Zhong, X.,Su, Y.,Zhou, Z.,Sun, Y.,Hou, Y.,Shao, F.,Ding, J.
Exosite-mediated targeting of GSDMB by dimeric granzyme A in lymphocyte pyroptotic killing.
Immunity, 59:257-, 2026

PubMed Abstract: In cellular immunity, cytotoxic lymphocytes employ granzyme A (GZMA) to cleave and activate the pore-forming protein gasdermin B (GSDMB) for the pyroptotic killing of target cells. How GZMA recognizes and cleaves GSDMB is unknown. Here, we show that human GZMA targets GSDMB via specific, high-affinity binding to its autoinhibitory GSDMB-C domain. This binding requires the dimerization of GZMA, a unique property among human granzymes. A crystal structure of the GZMA-GSDMB-C complex shows a 2:2 stoichiometry, featuring an exosite at each of the two symmetric dimer interfaces in GZMA. The exosite engages a two-loop-organized site in the GSDMB-C domain, rendering a functional cleavage at Lys244 in GSDMB. Mouse GZMA (mGZMA) adopts a similar dimer structure, but its exosite is less efficient in engaging GSDMB. Mutation of the exosite enabled mGZMA to efficiently cleave and activate GSDMB. Our study reveals a substrate-targeting mechanism used by lymphocyte-derived granzymes to kill target cells.

PubMed: 41592574
DOI: 10.1016/j.immuni.2025.12.009

Experimental method

X-RAY DIFFRACTION (2.69 Å)