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- EMDB-52874: Cryo-EM structure of NLRP3 bound to the inhibitor BAL-1516 at 3.0... -

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Basic information

Entry
Database: EMDB / ID: EMD-52874
TitleCryo-EM structure of NLRP3 bound to the inhibitor BAL-1516 at 3.06 Ang resolution
Map data3D reconstruction of NLRP3 in complex with BAL-1516 sharpened with DeepEMhancer
Sample
  • Complex: Complex of human NLRP3 bound to the inhibitor BAL-1516
    • Protein or peptide: NACHT, LRR and PYD domains-containing protein 3
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: 3-ethoxy-~{N}-methyl-~{N}-[(1~{R})-1-(4-methyl-1~{H}-pyrazolo[4,3-c]pyridin-7-yl)ethyl]-4-(4-methyl-1,3-thiazol-2-yl)benzamide
KeywordsNLRP3 / NOD-like receptor / BAL compound / inhibitor / inflammasome / BAL-1516 / IMMUNE SYSTEM
Function / homology
Function and homology information


detection of biotic stimulus / molecular sensor activity / positive regulation of type 2 immune response / phosphatidylinositol phosphate binding / positive regulation of T-helper 2 cell differentiation / positive regulation of T-helper 2 cell cytokine production / interphase microtubule organizing center / NLRP3 inflammasome complex / peptidoglycan binding / NLRP3 inflammasome complex assembly ...detection of biotic stimulus / molecular sensor activity / positive regulation of type 2 immune response / phosphatidylinositol phosphate binding / positive regulation of T-helper 2 cell differentiation / positive regulation of T-helper 2 cell cytokine production / interphase microtubule organizing center / NLRP3 inflammasome complex / peptidoglycan binding / NLRP3 inflammasome complex assembly / cysteine-type endopeptidase activator activity / phosphatidylinositol-4-phosphate binding / negative regulation of non-canonical NF-kappaB signal transduction / osmosensory signaling pathway / negative regulation of interleukin-1 beta production / positive regulation of interleukin-4 production / pattern recognition receptor signaling pathway / negative regulation of acute inflammatory response / microtubule organizing center / The NLRP3 inflammasome / pyroptotic inflammatory response / Purinergic signaling in leishmaniasis infection / signaling adaptor activity / positive regulation of interleukin-1 beta production / cellular response to virus / protein maturation / defense response / Cytoprotection by HMOX1 / molecular condensate scaffold activity / negative regulation of inflammatory response / positive regulation of non-canonical NF-kappaB signal transduction / ADP binding / protein homooligomerization / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / positive regulation of inflammatory response / Metalloprotease DUBs / SARS-CoV-1 activates/modulates innate immune responses / cellular response to lipopolysaccharide / regulation of inflammatory response / DNA-binding transcription factor binding / sequence-specific DNA binding / molecular adaptor activity / protein-macromolecule adaptor activity / inflammatory response / Golgi membrane / innate immune response / apoptotic process / SARS-CoV-2 activates/modulates innate and adaptive immune responses / signal transduction / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / ATP hydrolysis activity / mitochondrion / DNA-templated transcription / extracellular region / ATP binding / membrane / identical protein binding / nucleus / 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 profile. / 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 profile. / NACHT nucleoside triphosphatase / NACHT domain / NACHT-NTPase 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 / 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: 3.06 Å
AuthorsTorp J / Wilhelmsen K / Hartman G / Hagelueken G / Geyer M
Funding support Germany, 2 items
OrganizationGrant numberCountry
German Research Foundation (DFG)GE 976/16-1 Germany
German Research Foundation (DFG)EXC2151-390873048 Germany
CitationJournal: To Be Published
Title: Inhibition of NLRP3 by a CNS-penetrating indazole scaffold
Authors: Torp J / Geyer M
History
DepositionFeb 21, 2025-
Header (metadata) releaseSep 2, 2026-
Map releaseSep 2, 2026-
UpdateSep 2, 2026-
Current statusSep 2, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_52874.png

Downloads & links

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Map

FileDownload / File: emd_52874.map.gz / Format: CCP4 / Size: 129.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotation3D reconstruction of NLRP3 in complex with BAL-1516 sharpened with DeepEMhancer
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.09 Å/pix.
x 324 pix.
= 354.24 Å		1.09 Å/pix.
x 324 pix.
= 354.24 Å		1.09 Å/pix.
x 324 pix.
= 354.24 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.09333 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.155
Minimum - Maximum-0.021874355 - 2.1035824
Average (Standard dev.)0.000621271 (±0.013495623)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions324324324
Spacing324324324
CellA=B=C: 354.24002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: NLRP3-BAL1516 half map A

Fileemd_52874_half_map_1.map
AnnotationNLRP3-BAL1516 half map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: NLRP3-BAL1516 half map B

Fileemd_52874_half_map_2.map
AnnotationNLRP3-BAL1516 half map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of human NLRP3 bound to the inhibitor BAL-1516

EntireName: Complex of human NLRP3 bound to the inhibitor BAL-1516
Components
  • Complex: Complex of human NLRP3 bound to the inhibitor BAL-1516
    • Protein or peptide: NACHT, LRR and PYD domains-containing protein 3
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: 3-ethoxy-~{N}-methyl-~{N}-[(1~{R})-1-(4-methyl-1~{H}-pyrazolo[4,3-c]pyridin-7-yl)ethyl]-4-(4-methyl-1,3-thiazol-2-yl)benzamide

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Supramolecule #1: Complex of human NLRP3 bound to the inhibitor BAL-1516

SupramoleculeName: Complex of human NLRP3 bound to the inhibitor BAL-1516
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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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: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 118.323531 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKMASTRCKL ARYLEDLEDV DLKKFKMHLE DYPPQKGCIP LPRGQTEKAD HVDLATLMID FNGEEKAWAM AVWIFAAINR RDLYEKAKR DEPKWGSDNA RVSNPTVICQ EDSIEEEWMG LLEYLSRISI CKMKKDYRKK YRKYVRSRFQ CIEDRNARLG E SVSLNKRY ...String:
MKMASTRCKL ARYLEDLEDV DLKKFKMHLE DYPPQKGCIP LPRGQTEKAD HVDLATLMID FNGEEKAWAM AVWIFAAINR RDLYEKAKR DEPKWGSDNA RVSNPTVICQ EDSIEEEWMG LLEYLSRISI CKMKKDYRKK YRKYVRSRFQ CIEDRNARLG E SVSLNKRY TRLRLIKEHR SQQEREQELL AIGKTKTCES PVSPIKMELL FDPDDEHSEP VHTVVFQGAA GIGKTILARK MM LDWASGT LYQDRFDYLF YIHCREVSLV TQRSLGDLIM SCCPDPNPPI HKIVRKPSRI LFLMDGFDEL QGAFDEHIGP LCT DWQKAE RGDILLSSLI RKKLLPEASL LITTRPVALE KLQHLLDHPR HVEILGFSEA KRKEYFFKYF SDEAQARAAF SLIQ ENEVL FTMCFIPLVC WIVCTGLKQQ MESGKSLAQT SKTTTAVYVF FLSSLLQPRG GSQEHGLCAH LWGLCSLAAD GIWNQ KILF EESDLRNHGL QKADVSAFLR MNLFQKEVDC EKFYSFIHMT FQEFFAAMYY LLEEEKEGRT NVPGSRLKLP SRDVTV LLE NYGKFEKGYL IFVVRFLFGL VNQERTSYLE KKLSCKISQQ IRLELLKWIE VKAKAKKLQI QPSQLELFYC LYEMQEE DF VQRAMDYFPK IEINLSTRMD HMVSSFCIEN CHRVESLSLG FLHNMPKEEE EEEKEGRHLD MVQCVLPSSS HAACSHGL V NSHLTSSFCR GLFSVLSTSQ SLTELDLSDN SLGDPGMRVL CETLQHPGCN IRRLWLGRCG LSHECCFDIS LVLSSNQKL VELDLSDNAL GDFGIRLLCV GLKHLLCNLK KLWLVSCCLT SACCQDLASV LSTSHSLTRL YVGENALGDS GVAILCEKAK NPQCNLQKL GLVNSGLTSV CCSALSSVLS TNQNLTHLYL RGNTLGDKGI KLLCEGLLHP DCKLQVLELD NCNLTSHCCW D LSTLLTSS QSLRKLSLGN NDLGDLGVMM FCEVLKQQSC LLQNLGLSEM YFNYETKSAL ETLQEEKPEL TVVFEPSW

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: 1 / 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: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #4: 3-ethoxy-~{N}-methyl-~{N}-[(1~{R})-1-(4-methyl-1~{H}-pyrazolo[4,3...

MacromoleculeName: 3-ethoxy-~{N}-methyl-~{N}-[(1~{R})-1-(4-methyl-1~{H}-pyrazolo[4,3-c]pyridin-7-yl)ethyl]-4-(4-methyl-1,3-thiazol-2-yl)benzamide
type: ligand / ID: 4 / Number of copies: 1 / Formula: A1I4G
Molecular weightTheoretical: 435.542 Da

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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

Concentration0.78 mg/mL
BufferpH: 7.5
Component:
ConcentrationNameFormula
50.0 mMHEPES
150.0 mMsodium chlorideNaCl
10.0 mMmagnesium chlorideMgCl2
0.5 mMTCEP
1.0 mMADP
0.01 mMBAL-1516
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 51.7 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7pzc

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.06 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 765958
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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