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- PDB-9dh3: Cryo-EM structure of NLRP3 complex with Compound C -

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Basic information

Entry
Database: PDB / ID: 9dh3
TitleCryo-EM structure of NLRP3 complex with Compound C
ComponentsMaltose/maltodextrin-binding periplasmic protein,NACHT, LRR and PYD domains-containing protein 3 chimera
KeywordsIMMUNE SYSTEM / NLRP3 Inflammasome / Small Molecule Inhibitors / and Drug Discovery
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 / pyroptotic inflammatory response / detection of maltose stimulus / 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 / Metalloprotease DUBs / 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 / SARS-CoV-1 activates/modulates innate immune responses / positive regulation of inflammatory response / 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
: / ADENOSINE-5'-DIPHOSPHATE / Maltose/maltodextrin-binding periplasmic protein / NACHT, LRR and PYD domains-containing protein 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.76 Å
AuthorsMatico, R. / Grauwen, K. / Van Gool, M. / Muratore, E.M. / Yu, X. / Abdiaj, I. / Adhikary, S. / Adriaensen, I. / Aranzazu, G.M. / Alcazar, J. ...Matico, R. / Grauwen, K. / Van Gool, M. / Muratore, E.M. / Yu, X. / Abdiaj, I. / Adhikary, S. / Adriaensen, I. / Aranzazu, G.M. / 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, M.L. / Martin, M.L. / Martinez, C. / Miller, R. / Munoz, F.M. / Nooyens, A. / Perez, L.B. / Perrier, M. / Pietrak, B. / Serre, J. / Sharma, S. / Somers, M. / Suarez, J. / Tresadern, G. / Trabanco, A.A. / Van den Bulck, D. / Van Hauwermeiren, F. / Varghese, T. / Vega, J.A. / Youssef, S.A. / Edwards, M.J. / Oehlrich, D. / Van Opdenbosch, N.
Funding support1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 25, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Maltose/maltodextrin-binding periplasmic protein,NACHT, LRR and PYD domains-containing protein 3 chimera
B: Maltose/maltodextrin-binding periplasmic protein,NACHT, LRR and PYD domains-containing protein 3 chimera
C: Maltose/maltodextrin-binding periplasmic protein,NACHT, LRR and PYD domains-containing protein 3 chimera
D: Maltose/maltodextrin-binding periplasmic protein,NACHT, LRR and PYD domains-containing protein 3 chimera
hetero molecules


Theoretical massNumber of molelcules
Total (without water)576,93716
Polymers571,3514
Non-polymers5,58612
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Maltose/maltodextrin-binding periplasmic protein,NACHT, LRR and PYD domains-containing protein 3 chimera / MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / Angiotensin/vasopressin ...MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / Angiotensin/vasopressin receptor AII/AVP-like / Caterpiller protein 1.1 / CLR1.1 / Cold-induced autoinflammatory syndrome 1 protein / Cryopyrin / PYRIN-containing APAF1-like protein 1


Mass: 142837.766 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Gene: malE, b4034, JW3994, NLRP3, C1orf7, CIAS1, NALP3, PYPAF1
Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P0AEX9, UniProt: Q96P20, Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement
#2: Chemical
ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#3: Chemical
ChemComp-A1A4L / 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


Mass: 354.386 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H14N6O2S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-CPS / 3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE / CHAPS


Mass: 614.877 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C32H58N2O7S / Comment: detergent*YM
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: N-terminal MBP Fusion of NLRP3 Lacking the PYD Domain / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 44.57 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.76 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 94472 / Symmetry type: POINT

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