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- EMDB-13687: Reconstruction of the apo state of the human NLRP3 decamer. -

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Basic information

Entry
Database: EMDB / ID: EMD-13687
TitleReconstruction of the apo state of the human NLRP3 decamer.
Map dataReconstruction of the apo state of the human NLRP3 decamer.
Sample
  • Complex: NLRP3 decamer
    • Protein or peptide: NLRP3
Function / homology
Function and homology information


molecular sensor activity / detection of biotic stimulus / phosphatidylinositol phosphate binding / positive regulation of T-helper 2 cell differentiation / NLRP3 inflammasome complex assembly / positive regulation of T-helper 2 cell cytokine production / interphase microtubule organizing center / cysteine-type endopeptidase activator activity / positive regulation of type 2 immune response / NLRP3 inflammasome complex ...molecular sensor activity / detection of biotic stimulus / phosphatidylinositol phosphate binding / positive regulation of T-helper 2 cell differentiation / NLRP3 inflammasome complex assembly / positive regulation of T-helper 2 cell cytokine production / interphase microtubule organizing center / cysteine-type endopeptidase activator activity / positive regulation of type 2 immune response / NLRP3 inflammasome complex / osmosensory signaling pathway / peptidoglycan binding / phosphatidylinositol-4-phosphate binding / negative regulation of non-canonical NF-kappaB signal transduction / pattern recognition receptor signaling pathway / negative regulation of interleukin-1 beta production / pyroptotic inflammatory response / positive regulation of interleukin-4 production / microtubule organizing center / negative regulation of acute inflammatory response / The NLRP3 inflammasome / Purinergic signaling in leishmaniasis infection / protein maturation / signaling adaptor activity / positive regulation of interleukin-1 beta production / molecular condensate scaffold activity / positive regulation of non-canonical NF-kappaB signal transduction / defense response / Cytoprotection by HMOX1 / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / protein homooligomerization / ADP binding / negative regulation of inflammatory response / cellular response to virus / Metalloprotease DUBs / positive regulation of inflammatory response / SARS-CoV-1 activates/modulates innate immune responses / positive regulation of NF-kappaB transcription factor activity / cellular response to lipopolysaccharide / regulation of inflammatory response / protein-macromolecule adaptor activity / DNA-binding transcription factor binding / molecular adaptor activity / sequence-specific DNA binding / inflammatory response / Golgi membrane / innate immune response / apoptotic process / SARS-CoV-2 activates/modulates innate and adaptive immune responses / endoplasmic reticulum / signal transduction / positive regulation of transcription by RNA polymerase II / ATP hydrolysis activity / mitochondrion / extracellular region / ATP binding / identical protein 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 / DAPIN domain profile. ...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 / DAPIN domain profile. / PAAD/DAPIN/Pyrin domain / PAAD/DAPIN/Pyrin domain / NACHT nucleoside triphosphatase / NACHT domain / NACHT-NTPase domain profile. / Leucine rich repeat, ribonuclease inhibitor type / Leucine Rich repeat / Death-like domain superfamily / 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 speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 9.6 Å
AuthorsHochheiser IV / Pilsl M / Hagelueken G / Engel C / Geyer M
Funding support Germany, 1 items
OrganizationGrant numberCountry
German Research Foundation (DFG)EXC2151-390873048 Germany
CitationJournal: Nature / Year: 2022
Title: Structure of the NLRP3 decamer bound to the cytokine release inhibitor CRID3.
Authors: Inga V Hochheiser / Michael Pilsl / Gregor Hagelueken / Jonas Moecking / Michael Marleaux / Rebecca Brinkschulte / Eicke Latz / Christoph Engel / Matthias Geyer /
Abstract: NLRP3 is an intracellular sensor protein that when activated by a broad spectrum of exogenous and endogenous stimuli leads to inflammasome formation and pyroptosis. The conformational states of NLRP3 ...NLRP3 is an intracellular sensor protein that when activated by a broad spectrum of exogenous and endogenous stimuli leads to inflammasome formation and pyroptosis. The conformational states of NLRP3 and the way antagonistic small molecules act at the molecular level remain poorly understood. Here we report the cryo-electron microscopy structures of full-length human NLRP3 in its native form and complexed with the inhibitor CRID3 (also named MCC950). Inactive, ADP-bound NLRP3 is a decamer composed of homodimers of intertwined leucine-rich repeat (LRR) domains that assemble back-to-back as pentamers. The NACHT domain is located at the apical axis of this spherical structure. One pyrin domain dimer is in addition formed inside the LRR cage. Molecular contacts between the concave sites of two opposing LRR domains are mediated by an acidic loop that extends from an LRR transition segment. Binding of CRID3 considerably stabilizes the NACHT and LRR domains relative to each other. CRID3 binds into a cleft, connecting four subdomains of the NACHT with the transition LRR. Its central sulfonylurea group interacts with the Walker A motif of the NLRP3 nucleotide-binding domain and is sandwiched between two arginine residues, which explains the specificity of NLRP3 for this chemical entity. With the determination of the binding site of this key therapeutic agent, specific targeting of NLRP3 for the treatment of autoinflammatory and autoimmune diseases and rational drug optimization is within reach.
History
DepositionOct 7, 2021-
Header (metadata) releaseFeb 16, 2022-
Map releaseFeb 16, 2022-
UpdateMay 4, 2022-
Current statusMay 4, 2022Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.004
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.004
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_13687.png

Downloads & links

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Map

FileDownload / File: emd_13687.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationReconstruction of the apo state of the human NLRP3 decamer.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.29 Å/pix.
x 240 pix.
= 309.6 Å		1.29 Å/pix.
x 240 pix.
= 309.6 Å		1.29 Å/pix.
x 240 pix.
= 309.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.29 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.00286 / Movie #1: 0.004
Minimum - Maximum-0.0011434525 - 0.013032306
Average (Standard dev.)0.0005825841 (±0.0016818315)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 309.59998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.291.291.29
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z309.600309.600309.600
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS240240240
D min/max/mean-0.0010.0130.001

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Supplemental data

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Sample components

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Entire : NLRP3 decamer

EntireName: NLRP3 decamer
Components
  • Complex: NLRP3 decamer
    • Protein or peptide: NLRP3

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Supramolecule #1: NLRP3 decamer

SupramoleculeName: NLRP3 decamer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
Molecular weightTheoretical: 1.2 MDa

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Macromolecule #1: NLRP3

MacromoleculeName: NLRP3 / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKMASTRCKL ARYLEDLEDV DLKKFKMHLE DYPPQKGCIP LPRGQTEKAD HVDLATLMID FNGEEKAWA MAVWIFAAIN RRDLYEKAKR DEPKWGSDNA RVSNPTVICQ EDSIEEEWMG L LEYLSRIS ICKMKKDYRK KYRKYVRSRF QCIEDRNARL GESVSLNKRY ...String:
MKMASTRCKL ARYLEDLEDV DLKKFKMHLE DYPPQKGCIP LPRGQTEKAD HVDLATLMID FNGEEKAWA MAVWIFAAIN RRDLYEKAKR DEPKWGSDNA RVSNPTVICQ EDSIEEEWMG L LEYLSRIS ICKMKKDYRK KYRKYVRSRF QCIEDRNARL GESVSLNKRY TRLRLIKEHR SQ QEREQEL LAIGKTKTCE SPVSPIKMEL LFDPDDEHSE PVHTVVFQGA AGIGKTILAR KMM LDWASG TLYQDRFDYL FYIHCREVSL VTQRSLGDLI MSCCPDPNPP IHKIVRKPSR ILFL MDGFD ELQGAFDEHI GPLCTDWQKA ERGDILLSSL IRKKLLPEAS LLITTRPVAL EKLQH LLDH PRHVEILGFS EAKRKEYFFK YFSDEAQARA AFSLIQENEV LFTMCFIPLV CWIVCT GLK QQMESGKSLA QTSKTTTAVY VFFLSSLLQP RGGSQEHGLC AHLWGLCSLA ADGIWNQ KI LFEESDLRNH GLQKADVSAF LRMNLFQKEV DCEKFYSFIH MTFQEFFAAM YYLLEEEK E GRTNVPGSRL KLPSRDVTVL LENYGKFEKG YLIFVVRFLF GLVNQERTSY LEKKLSCKI SQQIRLELLK WIEVKAKAKK LQIQPSQLEL FYCLYEMQEE DFVQRAMDYF PKIEINLSTR MDHMVSSFC IENCHRVESL SLGFLHNMPK EEEEEEKEGR HLDMVQCVLP SSSHAACSHG L VNSHLTSS FCRGLFSVLS TSQSLTELDL SDNSLGDPGM RVLCETLQHP GCNIRRLWLG RC GLSHECC FDISLVLSSN QKLVELDLSD NALGDFGIRL LCVGLKHLLC NLKKLWLVSC CLT SACCQD LASVLSTSHS LTRLYVGENA LGDSGVAILC EKAKNPQCNL QKLGLVNSGL TSVC CSALS SVLSTNQNLT HLYLRGNTLG DKGIKLLCEG LLHPDCKLQV LELDNCNLTS HCCWD LSTL LTSSQSLRKL SLGNNDLGDL GVMMFCEVLK QQSCLLQNLG LSEMYFNYET KSALET LQE EKPELTVVFE PSW

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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

Concentration0.01 mg/mL
BufferpH: 7.5
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: 40.63 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

Final reconstructionApplied symmetry - Point group: D5 (2x5 fold dihedral) / Resolution.type: BY AUTHOR / Resolution: 9.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 60407
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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