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- PDB-6vfe: Gasdermin D pore -

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Basic information

Entry
Database: PDB / ID: 6vfe
TitleGasdermin D pore
ComponentsGasdermin-D, N-terminal
KeywordsLIPID BINDING PROTEIN / Pore-forming protein
Function / homology
Function and homology information


pore complex assembly / : / Release of apoptotic factors from the mitochondria / wide pore channel activity / NLRP3 inflammasome complex / cardiolipin binding / Regulation of TLR by endogenous ligand / phosphatidic acid binding / Interleukin-1 processing / phosphatidylinositol-4-phosphate binding ...pore complex assembly / : / Release of apoptotic factors from the mitochondria / wide pore channel activity / NLRP3 inflammasome complex / cardiolipin binding / Regulation of TLR by endogenous ligand / phosphatidic acid binding / Interleukin-1 processing / phosphatidylinositol-4-phosphate binding / phosphatidylserine binding / pyroptotic inflammatory response / protein secretion / Pyroptosis / Purinergic signaling in leishmaniasis infection / phosphatidylinositol-4,5-bisphosphate binding / positive regulation of interleukin-1 beta production / mitochondrial membrane / protein homooligomerization / positive regulation of inflammatory response / specific granule lumen / tertiary granule lumen / defense response to Gram-negative bacterium / ficolin-1-rich granule lumen / defense response to Gram-positive bacterium / defense response to bacterium / inflammatory response / innate immune response / Neutrophil degranulation / extracellular space / extracellular region / nucleoplasm / membrane / plasma membrane / cytosol
Similarity search - Function
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: 3.9 Å
AuthorsXia, S. / Ruan, J. / Wu, H.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI139914 United States
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)DP1HD087988 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI124491 United States
CitationJournal: Nature / Year: 2021
Title: Gasdermin D pore structure reveals preferential release of mature interleukin-1.
Authors: Shiyu Xia / Zhibin Zhang / Venkat Giri Magupalli / Juan Lorenzo Pablo / Ying Dong / Setu M Vora / Longfei Wang / Tian-Min Fu / Matthew P Jacobson / Anna Greka / Judy Lieberman / Jianbin Ruan / Hao Wu /
Abstract: As organelles of the innate immune system, inflammasomes activate caspase-1 and other inflammatory caspases that cleave gasdermin D (GSDMD). Caspase-1 also cleaves inactive precursors of the ...As organelles of the innate immune system, inflammasomes activate caspase-1 and other inflammatory caspases that cleave gasdermin D (GSDMD). Caspase-1 also cleaves inactive precursors of the interleukin (IL)-1 family to generate mature cytokines such as IL-1β and IL-18. Cleaved GSDMD forms transmembrane pores to enable the release of IL-1 and to drive cell lysis through pyroptosis. Here we report cryo-electron microscopy structures of the pore and the prepore of GSDMD. These structures reveal the different conformations of the two states, as well as extensive membrane-binding elements including a hydrophobic anchor and three positively charged patches. The GSDMD pore conduit is predominantly negatively charged. By contrast, IL-1 precursors have an acidic domain that is proteolytically removed by caspase-1. When permeabilized by GSDMD pores, unlysed liposomes release positively charged and neutral cargoes faster than negatively charged cargoes of similar sizes, and the pores favour the passage of IL-1β and IL-18 over that of their precursors. Consistent with these findings, living-but not pyroptotic-macrophages preferentially release mature IL-1β upon perforation by GSDMD. Mutation of the acidic residues of GSDMD compromises this preference, hindering intracellular retention of the precursor and secretion of the mature cytokine. The GSDMD pore therefore mediates IL-1 release by electrostatic filtering, which suggests the importance of charge in addition to size in the transport of cargoes across this large channel.
History
DepositionJan 3, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 21, 2021Provider: repository / Type: Initial release
Revision 1.1May 5, 2021Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2May 12, 2021Group: Database references / Structure summary / Category: pdbx_database_related / struct / Item: _pdbx_database_related.details / _struct.title
Revision 2.0May 26, 2021Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Polymer sequence / Refinement description / Structure summary
Category: atom_site / em_software ...atom_site / em_software / entity / entity_name_com / entity_poly / entity_poly_seq / pdbx_poly_seq_scheme / pdbx_struct_assembly_prop / pdbx_struct_sheet_hbond / pdbx_validate_close_contact / pdbx_validate_rmsd_angle / pdbx_validate_torsion / refine_ls_restr / software / struct_conf / struct_ref_seq_dif / struct_sheet / struct_sheet_order / struct_sheet_range
Item: _em_software.category / _entity.formula_weight ..._em_software.category / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_mutation / _entity_name_com.name / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _entity_poly_seq.mon_id / _pdbx_poly_seq_scheme.auth_mon_id / _pdbx_poly_seq_scheme.mon_id / _pdbx_poly_seq_scheme.pdb_mon_id / _pdbx_struct_assembly_prop.value
Description: Sequence discrepancy
Details: Residues 191-193 in the original model were misassigned.
Provider: author / Type: Coordinate replacement
Revision 2.1Jun 9, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 2.2May 29, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
A: Gasdermin-D, N-terminal
B: Gasdermin-D, N-terminal
C: Gasdermin-D, N-terminal
D: Gasdermin-D, N-terminal
E: Gasdermin-D, N-terminal
F: Gasdermin-D, N-terminal
G: Gasdermin-D, N-terminal
H: Gasdermin-D, N-terminal
I: Gasdermin-D, N-terminal
J: Gasdermin-D, N-terminal
K: Gasdermin-D, N-terminal
L: Gasdermin-D, N-terminal
M: Gasdermin-D, N-terminal
N: Gasdermin-D, N-terminal
O: Gasdermin-D, N-terminal
P: Gasdermin-D, N-terminal
Q: Gasdermin-D, N-terminal
R: Gasdermin-D, N-terminal
S: Gasdermin-D, N-terminal
T: Gasdermin-D, N-terminal
U: Gasdermin-D, N-terminal
V: Gasdermin-D, N-terminal
W: Gasdermin-D, N-terminal
X: Gasdermin-D, N-terminal
Y: Gasdermin-D, N-terminal
Z: Gasdermin-D, N-terminal
a: Gasdermin-D, N-terminal
b: Gasdermin-D, N-terminal
c: Gasdermin-D, N-terminal
d: Gasdermin-D, N-terminal
e: Gasdermin-D, N-terminal
f: Gasdermin-D, N-terminal
g: Gasdermin-D, N-terminal


Theoretical massNumber of molelcules
Total (without water)886,05733
Polymers886,05733
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area120170 Å2
ΔGint-392 kcal/mol
Surface area365940 Å2

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Components

#1: Protein ...
Gasdermin-D, N-terminal / GSDMD-NT / hGSDMD-NTD


Mass: 26850.221 Da / Num. of mol.: 33 / Mutation: L192E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GSDMD, DFNA5L, GSDMDC1, FKSG10 / Production host: Escherichia coli (E. coli) / References: UniProt: P57764

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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-D / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 1 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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
Image recordingElectron dose: 63.25 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.1_4122: / Classification: refinement
EM software
IDNameCategory
7UCSF Chimeramodel fitting
13PHENIXmodel refinement
CTF correctionType: NONE
SymmetryPoint symmetry: C33 (33 fold cyclic)
3D reconstructionResolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 90222 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00363195
ELECTRON MICROSCOPYf_angle_d0.785569
ELECTRON MICROSCOPYf_dihedral_angle_d5.3798547
ELECTRON MICROSCOPYf_chiral_restr0.0469471
ELECTRON MICROSCOPYf_plane_restr0.00511253

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