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- EMDB-22075: Cryo-EM structure of NLRP1-DPP9-VbP complex -

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Basic information

Entry
Database: EMDB / ID: EMD-22075
TitleCryo-EM structure of NLRP1-DPP9-VbP 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
  • Ligand: [(2~{R})-1-[(2~{R})-2-azanyl-3-methyl-butanoyl]pyrrolidin-2-yl]boronic acid
KeywordsNLRP1 / DPP9 / inflammasome / Val-boroPro (VbP) / talabostat / innate immunity / IMMUNE SYSTEM
Function / homology
Function and homology information


NLRP1 inflammasome complex assembly / NLRP1 inflammasome complex / The NLRP1 inflammasome / NLRP3 inflammasome complex / self proteolysis / dipeptidyl-peptidase IV / cysteine-type endopeptidase activator activity / dipeptidyl-peptidase activity / Hydrolases; Acting on peptide bonds (peptidases) / negative regulation of programmed cell death ...NLRP1 inflammasome complex assembly / NLRP1 inflammasome complex / The NLRP1 inflammasome / NLRP3 inflammasome complex / self proteolysis / dipeptidyl-peptidase IV / cysteine-type endopeptidase activator activity / dipeptidyl-peptidase activity / Hydrolases; Acting on peptide bonds (peptidases) / negative regulation of programmed cell death / pattern recognition receptor signaling pathway / cysteine-type endopeptidase activator activity involved in apoptotic process / cellular response to UV-B / pattern recognition receptor activity / pyroptotic inflammatory response / cell leading edge / response to muramyl dipeptide / aminopeptidase activity / signaling adaptor activity / antiviral innate immune response / serine-type peptidase activity / intrinsic apoptotic signaling pathway / activation of innate immune response / positive regulation of interleukin-1 beta production / molecular condensate scaffold activity / protein homooligomerization / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / positive regulation of inflammatory response / peptidase activity / double-stranded RNA binding / regulation of inflammatory response / double-stranded DNA binding / neuron apoptotic process / regulation of apoptotic process / defense response to virus / microtubule / defense response to bacterium / inflammatory response / protein domain specific binding / apoptotic process / nucleolus / enzyme binding / signal transduction / ATP hydrolysis activity / proteolysis / nucleoplasm / ATP binding / identical protein binding / nucleus / cytoplasm / cytosol
Similarity search - Function
FIIND domain / Function to find / UPA-FIIND domain / FIIND domain profile. / CARD8/ASC/NALP1, CARD domain / Dipeptidyl peptidase 8 /9 ,N-terminal / Dipeptidyl peptidase 8 and 9 N-terminal / : / NACHT, LRR and PYD domains-containing protein, helical domain HD2 / NLRC4 helical domain HD2 ...FIIND domain / Function to find / UPA-FIIND domain / FIIND domain profile. / CARD8/ASC/NALP1, CARD domain / Dipeptidyl peptidase 8 /9 ,N-terminal / Dipeptidyl peptidase 8 and 9 N-terminal / : / 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 / : / Dipeptidylpeptidase IV, N-terminal domain / Dipeptidyl peptidase IV (DPP IV) N-terminal region / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / Leucine Rich repeat / Leucine Rich Repeat / Peptidase S9, prolyl oligopeptidase, catalytic domain / Prolyl oligopeptidase family / Death-like domain superfamily / Leucine-rich repeat profile. / 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: 2.9 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-
UpdateMay 28, 2025-
Current statusMay 28, 2025Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.01
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.01
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6x6c
  • Surface level: 0.01
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_22075.png

Downloads & links

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Map

FileDownload / File: emd_22075.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 400 pix.
= 330. Å		0.83 Å/pix.
x 400 pix.
= 330. Å		0.83 Å/pix.
x 400 pix.
= 330. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.00564 / Movie #1: 0.01
Minimum - Maximum-0.04700823 - 0.10395835
Average (Standard dev.)0.00008058418 (±0.0016833417)
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-0.0470.1040.000

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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
  • Ligand: [(2~{R})-1-[(2~{R})-2-azanyl-3-methyl-butanoyl]pyrrolidin-2-yl]boronic acid

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Supramolecule #1: DPP9-NLRP1 complex

SupramoleculeName: DPP9-NLRP1 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
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: 101.761984 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSYYHHHHHH DYDIPTTENL YFQGAMGSMA TTGTPTADRG DAAATDDPAA RFQVQKHSWD GLRSIIHGSR KYSGLIVNKA PHDFQFVQK TDESGPHSHR LYYLGMPYGS RENSLLYSEI PKKVRKEALL LLSWKQMLDH FQATPHHGVY SREEELLRER K RLGVFGIT ...String:
MSYYHHHHHH DYDIPTTENL YFQGAMGSMA TTGTPTADRG DAAATDDPAA RFQVQKHSWD GLRSIIHGSR KYSGLIVNKA PHDFQFVQK TDESGPHSHR LYYLGMPYGS RENSLLYSEI PKKVRKEALL LLSWKQMLDH FQATPHHGVY SREEELLRER K RLGVFGIT SYDFHSESGL FLFQASNSLF HCRDGGKNGF MVSPMKPLEI KTQCSGPRMD PKICPADPAF FSFINNSDLW VA NIETGEE RRLTFCHQGL SNVLDDPKSA GVATFVIQEE FDRFTGYWWC PTASWEGSEG LKTLRILYEE VDESEVEVIH VPS PALEER KTDSYRYPRT GSKNPKIALK LAEFQTDSQG KIVSTQEKEL VQPFSSLFPK VEYIARAGWT RDGKYAWAMF LDRP QQWLQ LVLLPPALFI PSTENEEQRL ASARAVPRNV QPYVVYEEVT NVWINVHDIF YPFPQSEGED ELCFLRANEC KTGFC HLYK VTAVLKSQGY DWSEPFSPGE DEFKCPIKEE IALTSGEWEV LARHGSKIWV NEETKLVYFQ GTKDTPLEHH LYVVSY EAA GEIVRLTTPG FSHSCSMSQN FDMFVSHYSS VSTPPCVHVY KLSGPDDDPL HKQPRFWASM MEAASCPPDY VPPEIFH FH TRSDVRLYGM IYKPHALQPG KKHPTVLFVY GGPQVQLVNN SFKGIKYLRL NTLASLGYAV VVIDGRGSCQ RGLRFEGA L KNQMGQVEIE DQVEGLQFVA EKYGFIDLSR VAIHGWSYGG FLSLMGLIHK PQVFKVAIAG APVTVWMAYD TGYTERYMD VPENNQHGYE AGSVALHVEK LPNEPNRLLI LHGFLDENVH FFHTNFLVSQ LIRAGKPYQL QIYPNERHSI RCPESGEHYE VTLLHFLQE YL

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: 166.069484 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 VLENPSFSPL GVLLKMIHNA LRFIPVTSVV LLYHRVHPEE VTFHLYLIPS DCSIRKAIDD LEMKFQFVRI HKPPP LTPL YMGCRYTVSG SGSGMLEILP KELELCYRSP GEDQLFSEFY VGHLGSGIRL QVKDKKDETL VWEALVKPGD LMPATT LIP PARIAVPSPL DAPQLLHFVD QYREQLIARV TSVEVVLDKL HGQVLSQEQY ERVLAENTRP SQMRKLFSLS QSWDRKC KD GLYQALKETH PHLIMELWEK GSKKGLLPLS S

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

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Macromolecule #3: [(2~{R})-1-[(2~{R})-2-azanyl-3-methyl-butanoyl]pyrrolidin-2-yl]bo...

MacromoleculeName: [(2~{R})-1-[(2~{R})-2-azanyl-3-methyl-butanoyl]pyrrolidin-2-yl]boronic acid
type: ligand / ID: 3 / Number of copies: 2 / Formula: GK2
Molecular weightTheoretical: 214.07 Da
Chemical component information

ChemComp-GK2:
[(2~{R})-1-[(2~{R})-2-azanyl-3-methyl-butanoyl]pyrrolidin-2-yl]boronic acid

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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 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 278 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recording#0 - Image recording ID: 1 / #0 - Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / #0 - Number grids imaged: 4 / #0 - Number real images: 3553 / #0 - Average exposure time: 2.0 sec. / #0 - Average electron dose: 52.0 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: 1954 / #1 - Average exposure time: 2.4 sec. / #1 - Average electron dose: 65.0 e/Å2 / #1 - Details: stage tilt 37 degrees
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: 2.2 µm / Nominal defocus min: -0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Image recording ID1
CTF correctionSoftware - Name: CTFFIND (ver. 9.03) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 205538
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION (ver. 3.1)
Final 3D classificationNumber classes: 5 / Avg.num./class: 50000 / Software - Name: RELION (ver. 3.1)
FSC plot (resolution estimation)

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