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- EMDB-46855: Cryo-EM structure of NLRP3 complex with Compound C -

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Basic information

Entry
Database: EMDB / ID: EMD-46855
TitleCryo-EM structure of NLRP3 complex with Compound C
Map data
Sample
  • Complex: N-terminal MBP Fusion of NLRP3 Lacking the PYD Domain
    • Protein or peptide: Maltose/maltodextrin-binding periplasmic protein,NACHT, LRR and PYD domains-containing protein 3 chimera
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: 2-[(4S)-5-ethyl-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl]-N-(pyrimidin-4-yl)acetamide
  • Ligand: 3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE
KeywordsNLRP3 Inflammasome / Small Molecule Inhibitors / and Drug Discovery / IMMUNE SYSTEM
Function / homology
Function and homology information


detection of biotic stimulus / molecular sensor activity / 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 / positive regulation of type 2 immune response / NLRP3 inflammasome complex / cysteine-type endopeptidase activator activity ...detection of biotic stimulus / molecular sensor activity / 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 / positive regulation of type 2 immune response / NLRP3 inflammasome complex / cysteine-type endopeptidase activator activity / peptidoglycan binding / osmosensory signaling pathway / 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 / detection of maltose stimulus / pyroptotic inflammatory response / positive regulation of interleukin-4 production / maltose transport complex / microtubule organizing center / negative regulation of acute inflammatory response / carbohydrate transport / The NLRP3 inflammasome / carbohydrate transmembrane transporter activity / maltose binding / maltose transport / maltodextrin transmembrane transport / Purinergic signaling in leishmaniasis infection / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / signaling adaptor activity / ATP-binding cassette (ABC) transporter complex / protein maturation / positive regulation of interleukin-1 beta production / cell chemotaxis / molecular condensate scaffold activity / positive regulation of non-canonical NF-kappaB signal transduction / defense response / positive regulation of NF-kappaB transcription factor activity / Cytoprotection by HMOX1 / ADP binding / protein homooligomerization / cellular response to virus / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / negative regulation of inflammatory response / Metalloprotease DUBs / positive regulation of inflammatory response / SARS-CoV-1 activates/modulates innate immune responses / outer membrane-bounded periplasmic space / cellular response to lipopolysaccharide / regulation of inflammatory response / protein-macromolecule adaptor activity / molecular adaptor activity / DNA-binding transcription factor binding / sequence-specific DNA binding / periplasmic space / inflammatory response / Golgi membrane / innate immune response / apoptotic process / DNA damage response / 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 / 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 / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein / Death-like domain superfamily / Leucine-rich repeat / Leucine-rich repeat domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Maltose/maltodextrin-binding periplasmic protein / NACHT, LRR and PYD domains-containing protein 3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.76 Å
AuthorsMatico R / Grauwen K / Van Gool M / Muratore EM / Yu X / Abdiaj I / Adhikary S / Adriaensen I / Aranzazu GM / Alcazar J ...Matico R / Grauwen K / Van Gool M / Muratore EM / Yu X / Abdiaj I / Adhikary S / Adriaensen I / Aranzazu GM / Alcazar J / Bassi M / Brisse E / Canellas S / Chaudhuri S / Chauhan D / Delgado F / Dieguez-Vazquez A / Du Jardin M / Eastham V / Finley M / Jacobs T / Keustermans K / Kuhn R / Llaveria J / Leenaerts J / Linares ML / Martin ML / Martinez C / Miller R / Munoz FM / Nooyens A / Perez LB / Perrier M / Pietrak B / Serre J / Sharma S / Somers M / Suarez J / Tresadern G / Trabanco AA / Van den Bulck D / Van Hauwermeiren F / Varghese T / Vega JA / Youssef SA / Edwards MJ / Oehlrich D / Van Opdenbosch N
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: EMBO Mol Med / Year: 2025
Title: Navigating from cellular phenotypic screen to clinical candidate: selective targeting of the NLRP3 inflammasome.
Authors: Rosalie Matico / Karolien Grauwen / Dhruv Chauhan / Xiaodi Yu / Irini Abdiaj / Suraj Adhikary / Ine Adriaensen / Garcia Molina Aranzazu / Jesus Alcázar / Michela Bassi / Ellen Brisse / ...Authors: Rosalie Matico / Karolien Grauwen / Dhruv Chauhan / Xiaodi Yu / Irini Abdiaj / Suraj Adhikary / Ine Adriaensen / Garcia Molina Aranzazu / Jesus Alcázar / Michela Bassi / Ellen Brisse / Santiago Cañellas / Shubhra Chaudhuri / Francisca Delgado / Alejandro Diéguez-Vázquez / Marc Du Jardin / Victoria Eastham / Michael Finley / Tom Jacobs / Ken Keustermans / Robert Kuhn / Josep Llaveria / Jos Leenaerts / Maria Lourdes Linares / Maria Luz Martín / Rosa Martín-Pérez / Carlos Martínez / Robyn Miller / Frances M Muñoz / Michael E Muratore / Amber Nooyens / Laura Perez-Benito / Mathieu Perrier / Beth Pietrak / Jef Serré / Sujata Sharma / Marijke Somers / Javier Suarez / Gary Tresadern / Andres A Trabanco / Dries Van den Bulck / Michiel Van Gool / Filip Van Hauwermeiren / Teena Varghese / Juan Antonio Vega / Sameh A Youssef / Matthew J Edwards / Daniel Oehlrich / Nina Van Opdenbosch /
Abstract: The NLRP3 inflammasome plays a pivotal role in host defense and drives inflammation against microbial threats, crystals, and danger-associated molecular patterns (DAMPs). Dysregulation of NLRP3 ...The NLRP3 inflammasome plays a pivotal role in host defense and drives inflammation against microbial threats, crystals, and danger-associated molecular patterns (DAMPs). Dysregulation of NLRP3 activity is associated with various human diseases, making it an attractive therapeutic target. Patients with NLRP3 mutations suffer from Cryopyrin-Associated Periodic Syndrome (CAPS) emphasizing the clinical significance of modulating NLRP3. In this study, we present the identification of a novel chemical class exhibiting selective and potent inhibition of the NLRP3 inflammasome. Through a comprehensive structure-activity relationship (SAR) campaign, we optimized the lead molecule, compound A, for in vivo applications. Extensive in vitro and in vivo characterization of compound A confirmed the high selectivity and potency positioning compound A as a promising clinical candidate for diseases associated with aberrant NLRP3 activity. This research contributes to the ongoing efforts in developing targeted therapies for conditions involving NLRP3-mediated inflammation, opening avenues for further preclinical and clinical investigations.
History
DepositionSep 3, 2024-
Header (metadata) releaseDec 25, 2024-
Map releaseDec 25, 2024-
UpdateJan 22, 2025-
Current statusJan 22, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46855.png

Downloads & links

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Map

FileDownload / File: emd_46855.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 300 pix.
= 312. Å		1.04 Å/pix.
x 300 pix.
= 312. Å		1.04 Å/pix.
x 300 pix.
= 312. Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.04 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.016
Minimum - Maximum-0.05900581 - 0.11198663
Average (Standard dev.)0.0005221377 (±0.0036919452)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 312.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_46855_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_46855_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : N-terminal MBP Fusion of NLRP3 Lacking the PYD Domain

EntireName: N-terminal MBP Fusion of NLRP3 Lacking the PYD Domain
Components
  • Complex: N-terminal MBP Fusion of NLRP3 Lacking the PYD Domain
    • Protein or peptide: Maltose/maltodextrin-binding periplasmic protein,NACHT, LRR and PYD domains-containing protein 3 chimera
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: 2-[(4S)-5-ethyl-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl]-N-(pyrimidin-4-yl)acetamide
  • Ligand: 3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE

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Supramolecule #1: N-terminal MBP Fusion of NLRP3 Lacking the PYD Domain

SupramoleculeName: N-terminal MBP Fusion of NLRP3 Lacking the PYD Domain / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Maltose/maltodextrin-binding periplasmic protein,NACHT, LRR and P...

MacromoleculeName: Maltose/maltodextrin-binding periplasmic protein,NACHT, LRR and PYD domains-containing protein 3 chimera
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
EC number: Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 142.837766 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: KIEEGKLVIW INGDKGYNGL AEVGKKFEKD TGIKVTVEHP DKLEEKFPQV AATGDGPDII FWAHDRFGGY AQSGLLAEIT PDKAFQDKL YPFTWDAVRY NGKLIAYPIA VEALSLIYNK DLLPNPPKTW EEIPALDKEL KAKGKSALMF NLQEPYFTWP L IAADGGYA ...String:
KIEEGKLVIW INGDKGYNGL AEVGKKFEKD TGIKVTVEHP DKLEEKFPQV AATGDGPDII FWAHDRFGGY AQSGLLAEIT PDKAFQDKL YPFTWDAVRY NGKLIAYPIA VEALSLIYNK DLLPNPPKTW EEIPALDKEL KAKGKSALMF NLQEPYFTWP L IAADGGYA FKYENGKYDI KDVGVDNAGA KAGLTFLVDL IKNKHMNADT DYSIAEAAFN KGETAMTING PWAWSNIDTS KV NYGVTVL PTFKGQPSKP FVGVLSAGIN AASPNKELAK EFLENYLLTD EGLEAVNKDK PLGAVALKSY EEELVKDPRI AAT MENAQK GEIMPNIPQM SAFWYAVRTA VINAASGRQT VDEALKDAQT YRKKYRKYVR SRFQCIEDRN ARLGESVSLN KRYT RLRLI KEHRSQQERE QELLAIGKTK TCESPVSPIK MELLFDPDDE HSEPVHTVVF QGAAGIGKTI LARKMMLDWA SGTLY QDRF DYLFYIHCRE VSLVTQRSLG DLIMSCCPDP NPPIHKIVRK PSRILFLMDG FDELQGAFDE HIGPLCTDWQ KAERGD ILL SSLIRKKLLP EASLLITTRP VALEKLQHLL DHPRHVEILG FSEAKRKEYF FKYFSDEAQA RAAFSLIQEN EVLFTMC FI PLVCWIVCTG LKQQMESGKS LAQTSKTTTA VYVFFLSSLL QPRGGSQEHG LCAHLWGLCS LAADGIWNQK ILFEESDL R NHGLQKADVS AFLRMNLFQK EVDCEKFYSF IHMTFQEFFA AMYYLLEEEK EGRTNVPGSR LKLPSRDVTV LLENYGKFE KGYLIFVVRF LFGLVNQERT SYLEKKLSCK ISQQIRLELL KWIEVKAKAK KLQIQPSQLE LFYCLYEMQE EDFVQRAMDY FPKIEINLS TRMDHMVSSF CIENCHRVES LSLGFLHNMP KEEEEEEKEG RHLDMVQCVL PSSSHAACSH GLVNSHLTSS F CRGLFSVL STSQSLTELD LSDNSLGDPG MRVLCETLQH PGCNIRRLWL GRCGLSHECC FDISLVLSSN QKLVELDLSD NA LGDFGIR LLCVGLKHLL CNLKKLWLVS CCLTSACCQD LASVLSTSHS LTRLYVGENA LGDSGVAILC EKAKNPQCNL QKL GLVNSG LTSVCCSALS SVLSTNQNLT HLYLRGNTLG DKGIKLLCEG LLHPDCKLQV LELDNCNLTS HCCWDLSTLL TSSQ SLRKL SLGNNDLGDL GVMMFCEVLK QQSCLLQNLG LSEMYFNYET KSALETLQEE KPELTVVFEP SW

UniProtKB: Maltose/maltodextrin-binding periplasmic protein, 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: 4 / 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: 2-[(4S)-5-ethyl-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazi...

MacromoleculeName: 2-[(4S)-5-ethyl-8-oxothieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-yl]-N-(pyrimidin-4-yl)acetamide
type: ligand / ID: 3 / Number of copies: 4 / Formula: A1A4L
Molecular weightTheoretical: 354.386 Da

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Macromolecule #4: 3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE

MacromoleculeName: 3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE
type: ligand / ID: 4 / Number of copies: 4 / Formula: CPS
Molecular weightTheoretical: 614.877 Da
Chemical component information

ChemComp-CPS:
3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE / detergent*YM

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 44.57 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.4000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.76 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 94472
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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