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- EMDB-22074: Cryo-EM structure of NLRP1-DPP9 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-22074
TitleCryo-EM structure of NLRP1-DPP9 complex
Map data
Sample
  • Complex: DPP9-NLRP1 complex
    • Protein or peptide: Dipeptidyl peptidase 9
  • Protein or peptide: NACHT, LRR and PYD domains-containing protein 1
  • Protein or peptide: NACHT, LRR and PYD domains-containing protein 1
KeywordsNLRP1 / DPP9 / inflammasome / Val-boroPro (VbP) / talabostat / innate immunity / IMMUNE SYSTEM
Function / homology
Function and homology information


NLRP1 inflammasome complex assembly / cysteine-type endopeptidase activator activity / NLRP1 inflammasome complex / canonical inflammasome complex / The NLRP1 inflammasome / dipeptidyl-peptidase IV / self proteolysis / dipeptidyl-peptidase activity / negative regulation of programmed cell death / Hydrolases; Acting on peptide bonds (peptidases) ...NLRP1 inflammasome complex assembly / cysteine-type endopeptidase activator activity / NLRP1 inflammasome complex / canonical inflammasome complex / The NLRP1 inflammasome / dipeptidyl-peptidase IV / self proteolysis / dipeptidyl-peptidase activity / negative regulation of programmed cell death / Hydrolases; Acting on peptide bonds (peptidases) / pattern recognition receptor activity / pattern recognition receptor signaling pathway / cellular response to UV-B / stress-activated protein kinase signaling cascade / pyroptosis / cell leading edge / antiviral innate immune response / cysteine-type endopeptidase activator activity involved in apoptotic process / response to muramyl dipeptide / signaling adaptor activity / aminopeptidase activity / molecular condensate scaffold activity / serine-type peptidase activity / positive regulation of interleukin-1 beta production / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / protein homooligomerization / positive regulation of inflammatory response / activation of cysteine-type endopeptidase activity involved in apoptotic process / : / double-stranded RNA binding / peptidase activity / regulation of inflammatory response / double-stranded DNA binding / defense response to virus / neuron apoptotic process / regulation of apoptotic process / microtubule / defense response to bacterium / protein domain specific binding / apoptotic process / nucleolus / enzyme binding / ATP hydrolysis activity / proteolysis / nucleoplasm / ATP binding / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
FIIND domain / Function to find / FIIND domain profile. / Dipeptidyl peptidase 8 /9 ,N-terminal / Dipeptidyl peptidase 8 and 9 N-terminal / 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 ...FIIND domain / Function to find / FIIND domain profile. / Dipeptidyl peptidase 8 /9 ,N-terminal / Dipeptidyl peptidase 8 and 9 N-terminal / 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 / Leucine rich repeat, ribonuclease inhibitor type / DAPIN domain / DAPIN domain profile. / PAAD/DAPIN/Pyrin domain / NACHT nucleoside triphosphatase / NACHT domain / NACHT-NTPase domain profile. / PAAD/DAPIN/Pyrin domain / Dipeptidylpeptidase IV, N-terminal domain / Dipeptidyl peptidase IV (DPP IV) N-terminal region / Leucine Rich repeat / Leucine Rich Repeat / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / Peptidase S9, prolyl oligopeptidase, catalytic domain / Prolyl oligopeptidase family / Leucine-rich repeat profile. / Death-like domain superfamily / Leucine-rich repeat / Leucine-rich repeat domain superfamily / Alpha/Beta hydrolase fold / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Dipeptidyl peptidase 9 / NACHT, LRR and PYD domains-containing protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsHollingsworth LR / Sharif H / Griswold AR / Fontana P / Mintseris J / Dagbay KB / Paulo JA / Gygi SP / Bachovchin DA / Wu H
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 Al124491 United States
CitationJournal: Nature / Year: 2021
Title: DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation.
Authors: L Robert Hollingsworth / Humayun Sharif / Andrew R Griswold / Pietro Fontana / Julian Mintseris / Kevin B Dagbay / Joao A Paulo / Steven P Gygi / Daniel A Bachovchin / Hao Wu /
Abstract: Nucleotide-binding domain and leucine-rich repeat pyrin-domain containing protein 1 (NLRP1) is an inflammasome sensor that mediates the activation of caspase-1 to induce cytokine maturation and ...Nucleotide-binding domain and leucine-rich repeat pyrin-domain containing protein 1 (NLRP1) is an inflammasome sensor that mediates the activation of caspase-1 to induce cytokine maturation and pyroptosis. Gain-of-function mutations of NLRP1 cause severe inflammatory diseases of the skin. NLRP1 contains a function-to-find domain that auto-proteolyses into noncovalently associated subdomains, and proteasomal degradation of the repressive N-terminal fragment of NLRP1 releases its inflammatory C-terminal fragment (NLRP1 CT). Cytosolic dipeptidyl peptidases 8 and 9 (hereafter, DPP8/DPP9) both interact with NLRP1, and small-molecule inhibitors of DPP8/DPP9 activate NLRP1 by mechanisms that are currently unclear. Here we report cryo-electron microscopy structures of the human NLRP1-DPP9 complex alone and with Val-boroPro (VbP), an inhibitor of DPP8/DPP9. The structures reveal a ternary complex that comprises DPP9, full-length NLRP1 and the NLRPT CT. The binding of the NLRP1 CT to DPP9 requires full-length NLRP1, which suggests that NLRP1 activation is regulated by the ratio of NLRP1 CT to full-length NLRP1. Activation of the inflammasome by ectopic expression of the NLRP1 CT is consistently rescued by co-expression of autoproteolysis-deficient full-length NLRP1. The N terminus of the NLRP1 CT inserts into the DPP9 active site, and VbP disrupts this interaction. Thus, VbP weakens the NLRP1-DPP9 interaction and accelerates degradation of the N-terminal fragment to induce inflammasome activation. Overall, these data demonstrate that DPP9 quenches low levels of NLRP1 CT and thus serves as a checkpoint for activation of the NLRP1 inflammasome.
History
DepositionMay 27, 2020-
Header (metadata) releaseMar 10, 2021-
Map releaseMar 10, 2021-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0184
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.0184
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6x6a
  • Surface level: 0.0184
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_22074.png

Downloads & links

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Map

FileDownload / File: emd_22074.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.825 Å
Density
Contour LevelBy AUTHOR: 0.0184 / Movie #1: 0.0184
Minimum - Maximum-0.050547384 - 0.11099255
Average (Standard dev.)0.00019395225 (±0.0022244928)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 330.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8250.8250.825
M x/y/z400400400
origin x/y/z0.0000.0000.000
length x/y/z330.000330.000330.000
α/β/γ90.00090.00090.000
start NX/NY/NZ-170-170-170
NX/NY/NZ340340340
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS400400400
D min/max/mean-0.0510.1110.000

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Supplemental data

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Sample components

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Entire : DPP9-NLRP1 complex

EntireName: DPP9-NLRP1 complex
Components
  • Complex: DPP9-NLRP1 complex
    • Protein or peptide: Dipeptidyl peptidase 9
  • Protein or peptide: NACHT, LRR and PYD domains-containing protein 1
  • Protein or peptide: NACHT, LRR and PYD domains-containing protein 1

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Supramolecule #1: DPP9-NLRP1 complex

SupramoleculeName: DPP9-NLRP1 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Dipeptidyl peptidase 9

MacromoleculeName: Dipeptidyl peptidase 9 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: dipeptidyl-peptidase IV
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 98.38432 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MATTGTPTAD RGDAAATDDP AARFQVQKHS WDGLRSIIHG SRKYSGLIVN KAPHDFQFVQ KTDESGPHSH RLYYLGMPYG SRENSLLYS EIPKKVRKEA LLLLSWKQML DHFQATPHHG VYSREEELLR ERKRLGVFGI TSYDFHSESG LFLFQASNSL F HCRDGGKN ...String:
MATTGTPTAD RGDAAATDDP AARFQVQKHS WDGLRSIIHG SRKYSGLIVN KAPHDFQFVQ KTDESGPHSH RLYYLGMPYG SRENSLLYS EIPKKVRKEA LLLLSWKQML DHFQATPHHG VYSREEELLR ERKRLGVFGI TSYDFHSESG LFLFQASNSL F HCRDGGKN GFMVSPMKPL EIKTQCSGPR MDPKICPADP AFFSFINNSD LWVANIETGE ERRLTFCHQG LSNVLDDPKS AG VATFVIQ EEFDRFTGYW WCPTASWEGS EGLKTLRILY EEVDESEVEV IHVPSPALEE RKTDSYRYPR TGSKNPKIAL KLA EFQTDS QGKIVSTQEK ELVQPFSSLF PKVEYIARAG WTRDGKYAWA MFLDRPQQWL QLVLLPPALF IPSTENEEQR LASA RAVPR NVQPYVVYEE VTNVWINVHD IFYPFPQSEG EDELCFLRAN ECKTGFCHLY KVTAVLKSQG YDWSEPFSPG EDEFK CPIK EEIALTSGEW EVLARHGSKI WVNEETKLVY FQGTKDTPLE HHLYVVSYEA AGEIVRLTTP GFSHSCSMSQ NFDMFV SHY SSVSTPPCVH VYKLSGPDDD PLHKQPRFWA SMMEAASCPP DYVPPEIFHF HTRSDVRLYG MIYKPHALQP GKKHPTV LF VYGGPQVQLV NNSFKGIKYL RLNTLASLGY AVVVIDGRGS CQRGLRFEGA LKNQMGQVEI EDQVEGLQFV AEKYGFID L SRVAIHGWSY GGFLSLMGLI HKPQVFKVAI AGAPVTVWMA YDTGYTERYM DVPENNQHGY EAGSVALHVE KLPNEPNRL LILHGFLDEN VHFFHTNFLV SQLIRAGKPY QLQIYPNERH SIRCPESGEH YEVTLLHFLQ EYL

UniProtKB: Dipeptidyl peptidase 9

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Macromolecule #2: NACHT, LRR and PYD domains-containing protein 1

MacromoleculeName: NACHT, LRR and PYD domains-containing protein 1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 136.327344 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAGGAWGRLA CYLEFLKKEE LKEFQLLLAN KAHSRSSSGE TPAQPEKTSG MEVASYLVAQ YGEQRAWDLA LHTWEQMGLR SLCAQAQEG AGHSPSFPYS PSEPHLGSPS QPTSTAVLMP WIHELPAGCT QGSERRVLRQ LPDTSGRRWR EISASLLYQA L PSSPDHES ...String:
MAGGAWGRLA CYLEFLKKEE LKEFQLLLAN KAHSRSSSGE TPAQPEKTSG MEVASYLVAQ YGEQRAWDLA LHTWEQMGLR SLCAQAQEG AGHSPSFPYS PSEPHLGSPS QPTSTAVLMP WIHELPAGCT QGSERRVLRQ LPDTSGRRWR EISASLLYQA L PSSPDHES PSQESPNAPT STAVLGSWGS PPQPSLAPRE QEAPGTQWPL DETSGIYYTE IREREREKSE KGRPPWAAVV GT PPQAHTS LQPHHHPWEP SVRESLCSTW PWKNEDFNQK FTQLLLLQRP HPRSQDPLVK RSWPDYVEEN RGHLIEIRDL FGP GLDTQE PRIVILQGAA GIGKSTLARQ VKEAWGRGQL YGDRFQHVFY FSCRELAQSK VVSLAELIGK DGTATPAPIR QILS RPERL LFILDGVDEP GWVLQEPSSE LCLHWSQPQP ADALLGSLLG KTILPEASFL ITARTTALQN LIPSLEQARW VEVLG FSES SRKEYFYRYF TDERQAIRAF RLVKSNKELW ALCLVPWVSW LACTCLMQQM KRKEKLTLTS KTTTTLCLHY LAQALQ AQP LGPQLRDLCS LAAEGIWQKK TLFSPDDLRK HGLDGAIIST FLKMGILQEH PIPLSYSFIH LCFQEFFAAM SYVLEDE KG RGKHSNCIID LEKTLEAYGI HGLFGASTTR FLLGLLSDEG EREMENIFHC RLSQGRNLMQ WVPSLQLLLQ PHSLESLH C LYETRNKTFL TQVMAHFEEM GMCVETDMEL LVCTFCIKFS RHVKKLQLIE GRQHRSTWSP TMVVLFRWVP VTDAYWQIL FSVLKVTRNL KELDLSGNSL SHSAVKSLCK TLRRPRCLLE TLRLAGCGLT AEDCKDLAFG LRANQTLTEL DLSFNVLTDA GAKHLCQRL RQPSCKLQRL QLVSCGLTSD CCQDLASVLS ASPSLKELDL QQNNLDDVGV RLLCEGLRHP ACKLIRLGLD Q TTLSDEMR QELRALEQEK PQLLIFSRRK PSVMTPTEGL DTGEMSNSTS SLKRQRLGSE RAASHVAQAN LKLLDVSKIF PI AEIAEES SPEVVPVELL CVPSPASQGD LHTKPLGTDD DFWGPTGPVA TEVVDKEKNL YRVHFPVAGS YRWPNTGLCF VMR EAVTVE IEFCVWDQFL GEINPQHSWM VAGPLLDIKA EPGAVEAVHL PHFVALQGGH VDTSLFQMAH FKEEGMLLEK PARV ELHHI VLENPSF

UniProtKB: NACHT, LRR and PYD domains-containing protein 1

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Macromolecule #3: NACHT, LRR and PYD domains-containing protein 1

MacromoleculeName: NACHT, LRR and PYD domains-containing protein 1 / type: protein_or_peptide / ID: 3 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 29.76074 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SPLGVLLKMI HNALRFIPVT SVVLLYHRVH PEEVTFHLYL IPSDCSIRKA IDDLEMKFQF VRIHKPPPLT PLYMGCRYTV SGSGSGMLE ILPKELELCY RSPGEDQLFS EFYVGHLGSG IRLQVKDKKD ETLVWEALVK PGDLMPATTL IPPARIAVPS P LDAPQLLH ...String:
SPLGVLLKMI HNALRFIPVT SVVLLYHRVH PEEVTFHLYL IPSDCSIRKA IDDLEMKFQF VRIHKPPPLT PLYMGCRYTV SGSGSGMLE ILPKELELCY RSPGEDQLFS EFYVGHLGSG IRLQVKDKKD ETLVWEALVK PGDLMPATTL IPPARIAVPS P LDAPQLLH FVDQYREQLI ARVTSVEVVL DKLHGQVLSQ EQYERVLAEN TRPSQMRKLF SLSQSWDRKC KDGLYQALKE TH PHLIMEL WEKGSKKGLL PLSS

UniProtKB: NACHT, LRR and PYD domains-containing protein 1

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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

Concentration0.5 mg/mL
BufferpH: 7.5 / Details: 25 mM Tris pH 7.5, 150 mM NaCl, 1 mM TCEP
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 400 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 278 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: OTHER
Electron opticsCalibrated magnification: 10500 / Illumination mode: SPOT SCAN / Imaging mode: OTHER / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: -1.0 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recording#0 - Image recording ID: 1 / #0 - Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / #0 - Number grids imaged: 7 / #0 - Number real images: 7840 / #0 - Average exposure time: 1.8 sec. / #0 - Average electron dose: 67.54 e/Å2 / #0 - Details: stage tilt 0 degrees / #1 - Image recording ID: 2 / #1 - Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / #1 - Number grids imaged: 4 / #1 - Number real images: 1916 / #1 - Average exposure time: 2.6 sec. / #1 - Average electron dose: 67.6 e/Å2 / #1 - Details: stage tilt 37 degrees
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 11197166
Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
Final 3D classificationNumber classes: 5 / Avg.num./class: 50000 / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION (ver. 3.1)
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 179306
Image recording ID1
FSC plot (resolution estimation)

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