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- EMDB-32120: Cryo-EM structure of mouse NLRP3 (full-length) dodecamer -

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Basic information

Entry
Database: EMDB / ID: EMD-32120
TitleCryo-EM structure of mouse NLRP3 (full-length) dodecamer
Map datacryo-EM map of mouse NLRP3 dodecamer
Sample
  • Complex: Mouse NLRP3 (full-length) dodecamer
    • Protein or peptide: NACHT, LRR and PYD domains-containing protein 3
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: 1-[4-(2-oxidanylpropan-2-yl)furan-2-yl]sulfonyl-3-(1,2,3,5-tetrahydro-s-indacen-4-yl)urea
KeywordsNLR / NOD-like receptor / NLRP3 / Inflammasome / IMMUNE SYSTEM
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 / canonical inflammasome complex / positive regulation of T-helper 2 cell differentiation / NLRP3 inflammasome complex assembly / positive regulation of T-helper 2 cell cytokine production ...The NLRP3 inflammasome / positive regulation of T-helper 17 cell differentiation / Metalloprotease DUBs / detection of biotic stimulus / molecular sensor activity / phosphatidylinositol phosphate binding / canonical inflammasome complex / positive regulation of T-helper 2 cell differentiation / NLRP3 inflammasome complex assembly / positive regulation of T-helper 2 cell cytokine production / acute inflammatory response / interphase microtubule organizing center / positive regulation of cytokine production involved in immune response / positive regulation of type 2 immune response / NLRP3 inflammasome complex / leukocyte migration involved in inflammatory response / positive regulation of interleukin-13 production / positive regulation of interleukin-5 production / cellular response to peptidoglycan / osmosensory signaling pathway / phosphatidylinositol-4-phosphate binding / negative regulation of non-canonical NF-kappaB signal transduction / pattern recognition receptor signaling pathway / pyroptotic inflammatory response / positive regulation of interleukin-4 production / microtubule organizing center / signaling adaptor activity / positive regulation of interleukin-1 beta production / : / ADP binding / protein homooligomerization / 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 / DNA-binding transcription factor binding / defense response to virus / sequence-specific DNA 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 / nucleus / membrane / cytosol / cytoplasm
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 / DAPIN domain / NACHT nucleoside triphosphatase ...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 / DAPIN domain / NACHT nucleoside triphosphatase / NACHT domain / DAPIN domain profile. / NACHT-NTPase domain profile. / 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
NACHT, LRR and PYD domains-containing protein 3
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.55 Å
AuthorsOhto U / Shimizu T
Funding support Japan, 4 items
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, 2021-
Header (metadata) releaseMar 9, 2022-
Map releaseMar 9, 2022-
UpdateNov 20, 2024-
Current statusNov 20, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.01
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.01
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7vtq
  • Surface level: 0.01
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7vtq
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_32120.png

Downloads & links

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Map

FileDownload / File: emd_32120.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcryo-EM map of mouse NLRP3 dodecamer
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.25 Å/pix.
x 240 pix.
= 298.8 Å		1.25 Å/pix.
x 240 pix.
= 298.8 Å		1.25 Å/pix.
x 240 pix.
= 298.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.245 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.01 / Movie #1: 0.01
Minimum - Maximum-0.016758071 - 0.047203977
Average (Standard dev.)0.0004643201 (±0.0035844578)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 298.8 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.2451.2451.245
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z298.800298.800298.800
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ330330330
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS240240240
D min/max/mean-0.0170.0470.000

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Supplemental data

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Sample components

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Entire : Mouse NLRP3 (full-length) dodecamer

EntireName: Mouse NLRP3 (full-length) dodecamer
Components
  • Complex: Mouse NLRP3 (full-length) dodecamer
    • Protein or peptide: NACHT, LRR and PYD domains-containing protein 3
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: 1-[4-(2-oxidanylpropan-2-yl)furan-2-yl]sulfonyl-3-(1,2,3,5-tetrahydro-s-indacen-4-yl)urea

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Supramolecule #1: Mouse NLRP3 (full-length) dodecamer

SupramoleculeName: Mouse NLRP3 (full-length) dodecamer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)

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

MacromoleculeName: NACHT, LRR and PYD domains-containing protein 3 / type: protein_or_peptide / ID: 1 / Number of copies: 12 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 121.415977 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: HHHHHHDYKD DDDKLEVLFQ GPEFMTSVRC KLAQYLEDLE DVDLKKFKMH LEDYPPEKGC IPVPRGQMEK ADHLDLATLM IDFNGEEKA WAMAVWIFAA INRRDLWEKA KKDQPEWNDT CTSHSSMVCQ EDSLEEEWMG LLGYLSRISI CKKKKDYCKM Y RRHVRSRF ...String:
HHHHHHDYKD DDDKLEVLFQ GPEFMTSVRC KLAQYLEDLE DVDLKKFKMH LEDYPPEKGC IPVPRGQMEK ADHLDLATLM IDFNGEEKA WAMAVWIFAA INRRDLWEKA KKDQPEWNDT CTSHSSMVCQ EDSLEEEWMG LLGYLSRISI CKKKKDYCKM Y RRHVRSRF YSIKDRNARL GESVDLNSRY TQLQLVKEHP SKQEREHELL TIGRTKMRDS PMSSLKLELL FEPEDGHSEP VH TVVFQGA AGIGKTILAR KIMLDWALGK LFKDKFDYLF FIHCREVSLR TPRSLADLIV SCWPDPNPPV CKILRKPSRI LFL MDGFDE LQGAFDEHIG EVCTDWQKAV RGDILLSSLI RKKLLPKASL LITTRPVALE KLQHLLDHPR HVEILGFSEA KRKE YFFKY FSNELQAREA FRLIQENEVL FTMCFIPLVC WIVCTGLKQQ METGKSLAQT SKTTTAVYVF FLSSLLQSRG GIEEH LFSD YLQGLCSLAA DGIWNQKILF EECDLRKHGL QKTDVSAFLR MNVFQKEVDC ERFYSFSHMT FQEFFAAMYY LLEEEA EGE TVRKGPGGCS DLLNRDVKVL LENYGKFEKG YLIFVVRFLF GLVNQERTSY LEKKLSCKIS QQVRLELLKW IEVKAKA KK LQWQPSQLEL FYCLYEMQEE DFVQSAMDHF PKIEINLSTR MDHVVSSFCI KNCHRVKTLS LGFFHNSPKE EEEERRGG R PLDQVQCVFP DTHVACSSRL VNCCLTSSFC RGLFSSLSTN RSLTELDLSD NTLGDPGMRV LCEALQHPGC NIQRLWLGR CGLSHQCCFD ISSVLSSSQK LVELDLSDNA LGDFGIRLLC VGLKHLLCNL QKLWLVSCCL TSACCQDLAL VLSSNHSLTR LYIGENALG DSGVQVLCEK MKDPQCNLQK LGLVNSGLTS ICCSALTSVL KTNQNFTHLY LRSNALGDTG LRLLCEGLLH P DCKLQMLE LDNCSLTSHS CWNLSTILTH NHSLRKLNLG NNDLGDLCVV TLCEVLKQQG CLLQSLQLGE MYLNRETKRA LE ALQEEKP ELTIVFEISW

UniProtKB: NACHT, LRR and PYD domains-containing protein 3

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Macromolecule #2: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 12 / Formula: ADP
Molecular weightTheoretical: 427.201 Da
Chemical component information

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

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Macromolecule #3: 1-[4-(2-oxidanylpropan-2-yl)furan-2-yl]sulfonyl-3-(1,2,3,5-tetrah...

MacromoleculeName: 1-[4-(2-oxidanylpropan-2-yl)furan-2-yl]sulfonyl-3-(1,2,3,5-tetrahydro-s-indacen-4-yl)urea
type: ligand / ID: 3 / Number of copies: 12 / Formula: 7YN
Molecular weightTheoretical: 402.464 Da
Chemical component information

ChemComp-7YN:
1-[4-(2-oxidanylpropan-2-yl)furan-2-yl]sulfonyl-3-(1,2,3,5-tetrahydro-s-indacen-4-yl)urea

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 68.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: D6 (2x6 fold dihedral) / Resolution.type: BY AUTHOR / Resolution: 3.55 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 73930
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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