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- PDB-7vtq: Cryo-EM structure of mouse NLRP3 (full-length) dodecamer -

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Basic information

Entry
Database: PDB / ID: 7vtq
TitleCryo-EM structure of mouse NLRP3 (full-length) dodecamer
ComponentsNACHT, LRR and PYD domains-containing protein 3
KeywordsIMMUNE SYSTEM / NLR / NOD-like receptor / NLRP3 / Inflammasome
Function / homology
Function and homology information


The NLRP3 inflammasome / positive regulation of T-helper 17 cell differentiation / Metalloprotease DUBs / detection of biotic stimulus / molecular sensor activity / phosphatidylinositol phosphate binding / positive regulation of T-helper 2 cell differentiation / canonical inflammasome complex / positive regulation of T-helper 2 cell cytokine production / acute inflammatory response ...The NLRP3 inflammasome / positive regulation of T-helper 17 cell differentiation / Metalloprotease DUBs / detection of biotic stimulus / molecular sensor activity / phosphatidylinositol phosphate binding / positive regulation of T-helper 2 cell differentiation / canonical inflammasome complex / positive regulation of T-helper 2 cell cytokine production / acute inflammatory response / positive regulation of interleukin-18 production / interphase microtubule organizing center / positive regulation of type 2 immune response / positive regulation of cytokine production involved in immune response / NLRP3 inflammasome complex assembly / NLRP3 inflammasome complex / cellular response to peptidoglycan / positive regulation of interleukin-5 production / positive regulation of interleukin-13 production / interleukin-18-mediated signaling pathway / cysteine-type endopeptidase activator activity / osmosensory signaling pathway / phosphatidylinositol-4-phosphate binding / negative regulation of non-canonical NF-kappaB signal transduction / interleukin-1-mediated signaling pathway / pattern recognition receptor signaling pathway / negative regulation of interleukin-1 beta production / positive regulation of interleukin-4 production / negative regulation of acute inflammatory response / positive regulation of NLRP3 inflammasome complex assembly / microtubule organizing center / pyroptotic inflammatory response / protein secretion / signaling adaptor activity / positive regulation of interleukin-1 beta production / protein maturation / molecular condensate scaffold activity / positive regulation of non-canonical NF-kappaB signal transduction / ADP binding / protein homooligomerization / cellular response to virus / negative regulation of inflammatory response / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / positive regulation of inflammatory response / cellular response to lipopolysaccharide / regulation of inflammatory response / molecular adaptor activity / defense response to virus / sequence-specific DNA binding / protein-macromolecule adaptor activity / DNA-binding transcription factor binding / response to ethanol / defense response to Gram-positive bacterium / inflammatory response / Golgi membrane / innate immune response / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / ATP hydrolysis activity / mitochondrion / extracellular region / ATP binding / membrane / identical protein binding / nucleus / cytoplasm / cytosol
Similarity search - Function
NACHT-associated domain / Fish-specific NACHT associated domain / Fish-specific NACHT associated domain / : / NACHT, LRR and PYD domains-containing protein, helical domain HD2 / NLRC4 helical domain HD2 / NOD2, winged helix domain / NOD2 winged helix domain / NACHT nucleoside triphosphatase / NACHT domain ...NACHT-associated domain / Fish-specific NACHT associated domain / Fish-specific NACHT associated domain / : / NACHT, LRR and PYD domains-containing protein, helical domain HD2 / NLRC4 helical domain HD2 / NOD2, winged helix domain / NOD2 winged helix domain / NACHT nucleoside triphosphatase / NACHT domain / NACHT-NTPase domain profile. / DAPIN domain profile. / DAPIN domain / PAAD/DAPIN/Pyrin domain / PAAD/DAPIN/Pyrin domain / Leucine rich repeat, ribonuclease inhibitor type / Leucine Rich repeat / Death-like domain superfamily / Leucine-rich repeat profile. / Leucine-rich repeat / Leucine-rich repeat domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-7YN / ADENOSINE-5'-DIPHOSPHATE / NACHT, LRR and PYD domains-containing protein 3
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.55 Å
AuthorsOhto, U. / Shimizu, T.
Funding support Japan, 4items
OrganizationGrant numberCountry
Ministry of Education, Culture, Sports, Science and Technology (Japan)19H03164 Japan
Ministry of Education, Culture, Sports, Science and Technology (Japan)20K16274 Japan
Ministry of Education, Culture, Sports, Science and Technology (Japan)20K15730 Japan
Ministry of Education, Culture, Sports, Science and Technology (Japan)19H00976 Japan
CitationJournal: Proc Natl Acad Sci U S A / Year: 2022
Title: Structural basis for the oligomerization-mediated regulation of NLRP3 inflammasome activation.
Authors: Umeharu Ohto / Yukie Kamitsukasa / Hanako Ishida / Zhikuan Zhang / Karin Murakami / Chie Hirama / Sakiko Maekawa / Toshiyuki Shimizu /
Abstract: SignificanceThe nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) is a pattern recognition receptor that forms an inflammasome. The cryo-electron ...SignificanceThe nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) is a pattern recognition receptor that forms an inflammasome. The cryo-electron microscopy structure of the dodecameric form of full-length NLRP3 bound to the clinically relevant NLRP3-specific inhibitor MCC950 has established the structural basis for the oligomerization-mediated regulation of NLRP3 inflammasome activation and the mechanism of action of the NLRP3 specific inhibitor. The inactive NLRP3 oligomer represents the NLRP3 resting state, capable of binding to membranes and is likely disrupted for its activation. Visualization of the inhibitor binding mode will enable optimization of the activity of NLRP3 inflammasome inhibitor drugs.
History
DepositionOct 30, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 9, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Nov 20, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Assembly

Deposited unit
A: NACHT, LRR and PYD domains-containing protein 3
B: NACHT, LRR and PYD domains-containing protein 3
C: NACHT, LRR and PYD domains-containing protein 3
D: NACHT, LRR and PYD domains-containing protein 3
E: NACHT, LRR and PYD domains-containing protein 3
F: NACHT, LRR and PYD domains-containing protein 3
G: NACHT, LRR and PYD domains-containing protein 3
H: NACHT, LRR and PYD domains-containing protein 3
I: NACHT, LRR and PYD domains-containing protein 3
J: NACHT, LRR and PYD domains-containing protein 3
K: NACHT, LRR and PYD domains-containing protein 3
L: NACHT, LRR and PYD domains-containing protein 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)1,466,94836
Polymers1,456,99212
Non-polymers9,95624
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area30240 Å2
ΔGint-89 kcal/mol
Surface area395280 Å2

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Components

#1: Protein
NACHT, LRR and PYD domains-containing protein 3


Mass: 121415.977 Da / Num. of mol.: 12
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: NLRP3, NALP3 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8R4B8
#2: Chemical
ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#3: Chemical
ChemComp-7YN / 1-[4-(2-oxidanylpropan-2-yl)furan-2-yl]sulfonyl-3-(1,2,3,5-tetrahydro-s-indacen-4-yl)urea


Mass: 402.464 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C20H22N2O5S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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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: Mouse NLRP3 (full-length) dodecamer / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm) / Cell: ExpiSf9
Buffer solutionpH: 7.5
Details: 25 mM HEPES-NaOH (pH 7.5), 0.2 M NaCl, 1 mM MgCl2, 0.5 mM TCEP, 1.0 mM ADP, 0.05 mM MCC950
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: 68 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
SymmetryPoint symmetry: D6 (2x6 fold dihedral)
3D reconstructionResolution: 3.55 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 73930 / Symmetry type: POINT

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