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- EMDB-48288: Human NLRP3 complex with compound 2 in the closed hexamer -

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Basic information

Entry
Database: EMDB / ID: EMD-48288
TitleHuman NLRP3 complex with compound 2 in the closed hexamer
Map data
Sample
  • Complex: Human NLRP3 complex with compound 2
    • Protein or peptide: NACHT, LRR and PYD domains-containing protein 3
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: (2P)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol
KeywordsNLRP3 / cryo-EM / small molecule inhibitor / IMMUNE SYSTEM
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: 3.93 Å
AuthorsMammoliti O / Carbajo RJ / Perez-Benito L / Yu X
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: J Med Chem / Year: 2025
Title: Discovery of Potent and Brain-Penetrant Bicyclic NLRP3 Inhibitors with Peripheral and Central In Vivo Activity.
Authors: Oscar Mammoliti / Rodrigo Carbajo / Laura Perez-Benito / Xiaodi Yu / Marion L C Prieri / Leonardo Bontempi / Sofie Embrechts / Ine Paesmans / Michela Bassi / Anindya Bhattacharya / Santiago ...Authors: Oscar Mammoliti / Rodrigo Carbajo / Laura Perez-Benito / Xiaodi Yu / Marion L C Prieri / Leonardo Bontempi / Sofie Embrechts / Ine Paesmans / Michela Bassi / Anindya Bhattacharya / Santiago Cañellas / Saskia De Hoog / Samuël Demin / Harrie J M Gijsen / Geerwin Hache / Tom Jacobs / Soufyan Jerhaoui / Joseph Leenaerts / Ferdinand H Lutter / Michel Mahieu / Rosalie Matico / Robyn Miller / Daniel Oehlrich / Mathieu Perrier / Pavel Ryabchuk / Wim Schepens / Sujata Sharma / Marijke Somers / Javier Suarez / Michel Surkyn / Nina Van Opdenbosch / Tinne Verhulst / Astrid Bottelbergs /
Abstract: NLRP3 is a danger sensor protein responsible for inflammasome activation. This leads to pro-inflammatory cytokines release, like IL-1β, and pyroptosis, a regulated cell death. Mounting evidence ...NLRP3 is a danger sensor protein responsible for inflammasome activation. This leads to pro-inflammatory cytokines release, like IL-1β, and pyroptosis, a regulated cell death. Mounting evidence associates excessive NLRP3 activation to neurodegenerative conditions, such as Alzheimer's and Parkinson's diseases. Thus, NLRP3 inhibitors could potentially provide therapeutic benefit for these disorders. We describe here the evolution of inhibitors relying on a pyridazine-based motif for their key interactions with NLRP3. A Cryo-EM structure helped optimizing protein-ligand complementarity. Subsequently, conformational NMR studies pointed the efforts toward 5,6-bicyclic cores that allowed a balance between brain penetration and undesirable properties, such as hERG inhibition. The effort culminated in compound , which showed moderate (mouse) to good (rat) brain penetration and was active at low dose in an LPS challenge model. Importantly, an earlier compound was active in a central neuroinflammation model providing a valuable proof of concept for NLRP3 inhibition.
History
DepositionDec 12, 2024-
Header (metadata) releaseFeb 26, 2025-
Map releaseFeb 26, 2025-
UpdateMar 12, 2025-
Current statusMar 12, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48288.png

Downloads & links

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Map

FileDownload / File: emd_48288.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 320 pix.
= 266.24 Å		0.83 Å/pix.
x 320 pix.
= 266.24 Å		0.83 Å/pix.
x 320 pix.
= 266.24 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.832 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.141
Minimum - Maximum-2.633523 - 3.1779583
Average (Standard dev.)0.0075358297 (±0.055748764)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 266.24 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_48288_additional_1.map
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Half map: #1

Fileemd_48288_half_map_1.map
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Half map: #2

Fileemd_48288_half_map_2.map
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Sample components

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Entire : Human NLRP3 complex with compound 2

EntireName: Human NLRP3 complex with compound 2
Components
  • Complex: Human NLRP3 complex with compound 2
    • Protein or peptide: NACHT, LRR and PYD domains-containing protein 3
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: (2P)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

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Supramolecule #1: Human NLRP3 complex with compound 2

SupramoleculeName: Human NLRP3 complex with compound 2 / 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
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: 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'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 1 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

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Macromolecule #3: (2P)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-6,7-dihydro-5H-cyc...

MacromoleculeName: (2P)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol
type: ligand / ID: 3 / Number of copies: 1 / Formula: A1BLP
Molecular weightTheoretical: 392.418 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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 52.34 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: 0.8 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: 3.93 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 407363
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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