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- PDB-7wge: Human NLRP1 complexed with thioredoxin -

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Basic information

Entry
Database: PDB / ID: 7wge
TitleHuman NLRP1 complexed with thioredoxin
Components
  • NACHT, LRR and PYD domains-containing protein 1, N-terminus
  • Thioredoxin
KeywordsIMMUNE SYSTEM / NLRP1 / inflammasome / thioredoxin
Function / homology
Function and homology information


NLRP1 inflammasome complex assembly / cysteine-type endopeptidase activator activity / NLRP1 inflammasome complex / canonical inflammasome complex / The NLRP1 inflammasome / self proteolysis / Hydrolases; Acting on peptide bonds (peptidases) / pattern recognition receptor signaling pathway / pattern recognition receptor activity / cellular response to UV-B ...NLRP1 inflammasome complex assembly / cysteine-type endopeptidase activator activity / NLRP1 inflammasome complex / canonical inflammasome complex / The NLRP1 inflammasome / self proteolysis / Hydrolases; Acting on peptide bonds (peptidases) / pattern recognition receptor signaling pathway / pattern recognition receptor activity / cellular response to UV-B / pyroptotic inflammatory response / response to muramyl dipeptide / cysteine-type endopeptidase activator activity involved in apoptotic process / protein-disulfide reductase activity / signaling adaptor activity / antiviral innate immune response / positive regulation of interleukin-1 beta production / molecular condensate scaffold activity / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / protein homooligomerization / : / positive regulation of inflammatory response / double-stranded RNA binding / peptidase activity / regulation of inflammatory response / double-stranded DNA binding / defense response to virus / regulation of apoptotic process / neuron apoptotic process / defense response to bacterium / protein domain specific binding / nucleolus / apoptotic process / enzyme binding / signal transduction / ATP hydrolysis activity / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
FIIND domain / Function to find / FIIND domain profile. / CARD8/ASC/NALP1, CARD 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 ...FIIND domain / Function to find / FIIND domain profile. / CARD8/ASC/NALP1, CARD 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 / Thioredoxin / Leucine Rich repeat / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / Leucine Rich Repeat / Thioredoxin / Leucine-rich repeat profile. / Death-like domain superfamily / Thioredoxin domain profile. / Thioredoxin domain / Leucine-rich repeat / Leucine-rich repeat domain superfamily / Thioredoxin-like superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / Thioredoxin / NACHT, LRR and PYD domains-containing protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Spodoptera frugiperda (fall armyworm)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsZhang, Z. / Ohto, U. / Shimizu, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nature / Year: 2023
Title: Structural basis for thioredoxin-mediated suppression of NLRP1 inflammasome.
Authors: Zhikuan Zhang / Takuma Shibata / Akiko Fujimura / Jiro Kitaura / Kensuke Miyake / Umeharu Ohto / Toshiyuki Shimizu /
Abstract: Inflammasome sensors detect pathogen- and danger-associated molecular patterns and promote inflammation and pyroptosis. NLRP1 was the first inflammasome sensor to be described, and its ...Inflammasome sensors detect pathogen- and danger-associated molecular patterns and promote inflammation and pyroptosis. NLRP1 was the first inflammasome sensor to be described, and its hyperactivation is linked to autoinflammatory disease and cancer. However, the mechanism underlying the activation and regulation of NLRP1 has not been clearly elucidated. Here we identify ubiquitously expressed endogenous thioredoxin (TRX) as a binder of NLRP1 and a suppressor of the NLRP1 inflammasome. The cryo-electron microscopy structure of human NLRP1 shows NLRP1 bound to Spodoptera frugiperda TRX. Mutagenesis studies of NLRP1 and human TRX show that TRX in the oxidized form binds to the nucleotide-binding domain subdomain of NLRP1. This observation highlights the crucial role of redox-active cysteines of TRX in NLRP1 binding. Cellular assays reveal that TRX suppresses NLRP1 inflammasome activation and thus negatively regulates NLRP1. Our data identify the TRX system as an intrinsic checkpoint for innate immunity and provide opportunities for future therapeutic intervention in NLRP1 inflammasome activation targeting this system.
History
DepositionDec 28, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 5, 2023Provider: repository / Type: Initial release
Revision 1.1Sep 20, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Sep 27, 2023Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation_author.identifier_ORCID
Revision 1.3Oct 18, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.4Nov 20, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: NACHT, LRR and PYD domains-containing protein 1, N-terminus
B: Thioredoxin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,4924
Polymers113,9452
Non-polymers5482
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area2360 Å2
ΔGint-23 kcal/mol
Surface area36900 Å2

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Components

#1: Protein NACHT, LRR and PYD domains-containing protein 1, N-terminus / hNLRP1


Mass: 101999.953 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NLRP1, CARD7, DEFCAP, KIAA0926, NAC, NALP1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9C000
#2: Protein Thioredoxin


Mass: 11944.890 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Spodoptera frugiperda (fall armyworm) / References: UniProt: A0A2H1VFV3
#3: Chemical ChemComp-AGS / PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-GAMMA-S / ADENOSINE 5'-(3-THIOTRIPHOSPHATE) / ADENOSINE 5'-(GAMMA-THIOTRIPHOSPHATE) / ADENOSINE-5'-DIPHOSPHATE MONOTHIOPHOSPHATE


Mass: 523.247 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O12P3S / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP-gamma-S, energy-carrying molecule analogue*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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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

Component
IDNameTypeEntity IDParent-IDSource
1hNLRP1 complexed with sfTRXCOMPLEX#1-#20MULTIPLE SOURCES
2hNLRP1COMPLEX#11RECOMBINANT
3sfTRXCOMPLEX#21NATURAL
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
22Spodoptera frugiperda (fall armyworm)7108
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 63.2 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 72304 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0026593
ELECTRON MICROSCOPYf_angle_d0.6128934
ELECTRON MICROSCOPYf_dihedral_angle_d4.881891
ELECTRON MICROSCOPYf_chiral_restr0.041023
ELECTRON MICROSCOPYf_plane_restr0.0051133

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