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- PDB-8gtn: Cryo-EM structure of the gasdermin B pore -

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Basic information

Entry
Database: PDB / ID: 8gtn
TitleCryo-EM structure of the gasdermin B pore
ComponentsIsoform 4 of Gasdermin-B
KeywordsIMMUNE SYSTEM / Pyroptosis / Pore-forming
Function / homology
Function and homology information


cytotoxic T cell pyroptotic cell death / killing by host of symbiont cells / wide pore channel activity / programmed cell death / cardiolipin binding / phosphatidylinositol-4-phosphate binding / phosphatidylserine binding / pyroptotic inflammatory response / phosphatidylinositol-4,5-bisphosphate binding / phospholipid binding ...cytotoxic T cell pyroptotic cell death / killing by host of symbiont cells / wide pore channel activity / programmed cell death / cardiolipin binding / phosphatidylinositol-4-phosphate binding / phosphatidylserine binding / pyroptotic inflammatory response / phosphatidylinositol-4,5-bisphosphate binding / phospholipid binding / defense response to Gram-negative bacterium / killing of cells of another organism / defense response to bacterium / plasma membrane / cytoplasm
Similarity search - Function
Gasdermin / Gasdermin, PUB domain / Gasdermin PUB domain / Gasdermin, pore forming domain / Gasdermin pore forming domain
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.17 Å
AuthorsHou, Y.J. / Cheng, H. / Ding, J.
Funding support China, 1items
OrganizationGrant numberCountry
Chinese Academy of Sciences China
CitationJournal: Nature / Year: 2023
Title: Structural mechanisms for regulation of GSDMB pore-forming activity.
Authors: Xiu Zhong / Huan Zeng / Zhiwei Zhou / Ya Su / Hang Cheng / Yanjie Hou / Yang She / Na Feng / Jia Wang / Feng Shao / Jingjin Ding /
Abstract: Cytotoxic lymphocyte-derived granzyme A (GZMA) cleaves GSDMB, a gasdermin-family pore-forming protein, to trigger target cell pyroptosis. GSDMB and the charter gasdermin family member GSDMD have been ...Cytotoxic lymphocyte-derived granzyme A (GZMA) cleaves GSDMB, a gasdermin-family pore-forming protein, to trigger target cell pyroptosis. GSDMB and the charter gasdermin family member GSDMD have been inconsistently reported to be degraded by the Shigella flexneri ubiquitin-ligase virulence factor IpaH7.8 (refs. ). Whether and how IpaH7.8 targets both gasdermins is undefined, and the pyroptosis function of GSDMB has even been questioned recently. Here we report the crystal structure of the IpaH7.8-GSDMB complex, which shows how IpaH7.8 recognizes the GSDMB pore-forming domain. We clarify that IpaH7.8 targets human (but not mouse) GSDMD through a similar mechanism. The structure of full-length GSDMB suggests stronger autoinhibition than in other gasdermins. GSDMB has multiple splicing isoforms that are equally targeted by IpaH7.8 but exhibit contrasting pyroptotic activities. Presence of exon 6 in the isoforms dictates the pore-forming, pyroptotic activity in GSDMB. We determine the cryo-electron microscopy structure of the 27-fold-symmetric GSDMB pore and depict conformational changes that drive pore formation. The structure uncovers an essential role for exon-6-derived elements in pore assembly, explaining pyroptosis deficiency in the non-canonical splicing isoform used in recent studies. Different cancer cell lines have markedly different isoform compositions, correlating with the onset and extent of pyroptosis following GZMA stimulation. Our study illustrates fine regulation of GSDMB pore-forming activity by pathogenic bacteria and mRNA splicing and defines the underlying structural mechanisms.
History
DepositionSep 8, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 12, 2023Provider: repository / Type: Initial release
Revision 1.1May 3, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jul 3, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform 4 of Gasdermin-B
B: Isoform 4 of Gasdermin-B
C: Isoform 4 of Gasdermin-B
D: Isoform 4 of Gasdermin-B
E: Isoform 4 of Gasdermin-B
F: Isoform 4 of Gasdermin-B
G: Isoform 4 of Gasdermin-B
H: Isoform 4 of Gasdermin-B
I: Isoform 4 of Gasdermin-B
J: Isoform 4 of Gasdermin-B
K: Isoform 4 of Gasdermin-B
L: Isoform 4 of Gasdermin-B
M: Isoform 4 of Gasdermin-B
N: Isoform 4 of Gasdermin-B
O: Isoform 4 of Gasdermin-B
P: Isoform 4 of Gasdermin-B
Q: Isoform 4 of Gasdermin-B
R: Isoform 4 of Gasdermin-B
S: Isoform 4 of Gasdermin-B
T: Isoform 4 of Gasdermin-B
V: Isoform 4 of Gasdermin-B
W: Isoform 4 of Gasdermin-B
X: Isoform 4 of Gasdermin-B
Y: Isoform 4 of Gasdermin-B
Z: Isoform 4 of Gasdermin-B
AA: Isoform 4 of Gasdermin-B
BA: Isoform 4 of Gasdermin-B


Theoretical massNumber of molelcules
Total (without water)772,97527
Polymers772,97527
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein ...
Isoform 4 of Gasdermin-B / Gasdermin-like protein


Mass: 28628.705 Da / Num. of mol.: 27
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GSDMB, GSDML, PP4052, PRO2521 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q8TAX9

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Pore-forming protein gasdermin B / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 8
SpecimenConc.: 0.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.20.1_4487refinement
PHENIX1.20.1_4487refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.17 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 85337 / Symmetry type: POINT
RefinementCross valid method: NONE

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