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- EMDB-30501: Cryo-EM structure of human TLR7 in complex with UNC93B1 -

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Basic information

Entry
Database: EMDB / ID: EMD-30501
TitleCryo-EM structure of human TLR7 in complex with UNC93B1
Map data
Sample
  • Complex: Complex of TLR7 and UNC93B1
    • Protein or peptide: Toll-like receptor 7
    • Protein or peptide: Protein unc-93 homolog B1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information


UNC93B1 deficiency - HSE / Toll Like Receptor 7/8 (TLR7/8) Cascade / toll-like receptor 7 signaling pathway / T cell antigen processing and presentation / I-kappaB phosphorylation / MyD88 dependent cascade initiated on endosome / TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation / Toll-like receptor binding / toll-like receptor 3 signaling pathway / toll-like receptor 9 signaling pathway ...UNC93B1 deficiency - HSE / Toll Like Receptor 7/8 (TLR7/8) Cascade / toll-like receptor 7 signaling pathway / T cell antigen processing and presentation / I-kappaB phosphorylation / MyD88 dependent cascade initiated on endosome / TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation / Toll-like receptor binding / toll-like receptor 3 signaling pathway / toll-like receptor 9 signaling pathway / siRNA binding / early phagosome / endolysosome membrane / Trafficking and processing of endosomal TLR / pattern recognition receptor activity / toll-like receptor signaling pathway / canonical NF-kappaB signal transduction / positive regulation of interferon-alpha production / positive regulation of chemokine production / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / positive regulation of interleukin-12 production / positive regulation of interferon-beta production / positive regulation of interleukin-8 production / intracellular protein transport / regulation of protein phosphorylation / cell morphogenesis / positive regulation of inflammatory response / positive regulation of non-canonical NF-kappaB signal transduction / cellular response to mechanical stimulus / transmembrane signaling receptor activity / antigen processing and presentation of exogenous peptide antigen via MHC class II / positive regulation of interleukin-6 production / double-stranded RNA binding / positive regulation of type II interferon production / defense response to virus / Potential therapeutics for SARS / membrane => GO:0016020 / single-stranded RNA binding / lysosome / receptor complex / endosome membrane / endosome / inflammatory response / immune response / Golgi membrane / innate immune response / endoplasmic reticulum membrane / endoplasmic reticulum / plasma membrane / cytoplasm
Similarity search - Function
Protein unc-93 homolog B1 / BspA type Leucine rich repeat region / BspA type Leucine rich repeat region (6 copies) / Toll-like receptor / TIR domain / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Toll - interleukin 1 - resistance / TIR domain profile. / Toll/interleukin-1 receptor homology (TIR) domain ...Protein unc-93 homolog B1 / BspA type Leucine rich repeat region / BspA type Leucine rich repeat region (6 copies) / Toll-like receptor / TIR domain / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Toll - interleukin 1 - resistance / TIR domain profile. / Toll/interleukin-1 receptor homology (TIR) domain / Toll/interleukin-1 receptor homology (TIR) domain superfamily / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Leucine-rich repeat / Leucine-rich repeat domain superfamily
Similarity search - Domain/homology
Protein unc-93 homolog B1 / Toll-like receptor 7
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.2 Å
AuthorsOhto U / Ishida H / Shimizu T
CitationJournal: Nat Struct Mol Biol / Year: 2021
Title: Cryo-EM structures of Toll-like receptors in complex with UNC93B1.
Authors: Hanako Ishida / Jinta Asami / Zhikuan Zhang / Tomohiro Nishizawa / Hideki Shigematsu / Umeharu Ohto / Toshiyuki Shimizu /
Abstract: Nucleic acid-sensing Toll-like receptors (TLRs) play a pivotal role in innate immunity by recognizing foreign DNA and RNA. Compartmentalization of these TLRs in the endosome limits their activation ...Nucleic acid-sensing Toll-like receptors (TLRs) play a pivotal role in innate immunity by recognizing foreign DNA and RNA. Compartmentalization of these TLRs in the endosome limits their activation by self-derived nucleic acids and reduces the possibility of autoimmune reactions. Although chaperone Unc-93 homolog B1, TLR signaling regulator (UNC93B1) is indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome, mechanisms of UNC93B1-mediated TLR regulation remain largely unknown. Here, we report two cryo-EM structures of human and mouse TLR3-UNC93B1 complexes and a human TLR7-UNC93B1 complex. UNC93B1 exhibits structural similarity to the major facilitator superfamily transporters. Both TLRs interact with the UNC93B1 amino-terminal six-helix bundle through their transmembrane and luminal juxtamembrane regions, but the complexes of TLR3 and TLR7 with UNC93B1 differ in their oligomerization state. The structural information provided here should aid in designing compounds to combat autoimmune diseases.
History
DepositionSep 3, 2020-
Header (metadata) releaseJan 6, 2021-
Map releaseJan 6, 2021-
UpdateFeb 24, 2021-
Current statusFeb 24, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.016
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.016
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7cyn
  • Surface level: 0.016
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30501.png

Downloads & links

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Map

FileDownload / File: emd_30501.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.245 Å
Density
Contour LevelBy AUTHOR: 0.016 / Movie #1: 0.016
Minimum - Maximum-0.012433902 - 0.04099079
Average (Standard dev.)1.5544258e-05 (±0.00317263)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 249.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.2451.2451.245
M x/y/z200200200
origin x/y/z0.0000.0000.000
length x/y/z249.000249.000249.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS200200200
D min/max/mean-0.0120.0410.000

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Supplemental data

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Sample components

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Entire : Complex of TLR7 and UNC93B1

EntireName: Complex of TLR7 and UNC93B1
Components
  • Complex: Complex of TLR7 and UNC93B1
    • Protein or peptide: Toll-like receptor 7
    • Protein or peptide: Protein unc-93 homolog B1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Complex of TLR7 and UNC93B1

SupramoleculeName: Complex of TLR7 and UNC93B1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: Toll-like receptor 7

MacromoleculeName: Toll-like receptor 7 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 121.060586 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MVFPMWTLKR QILILFNIIL ISKLLGARWF PKTLPCDVTL DVPKNHVIVD CTDKHLTEIP GGIPTNTTNL TLTINHIPDI SPASFHRLD HLVEIDFRCN CVPIPLGSKN NMCIKRLQIK PRSFSGLTYL KSLYLDGNQL LEIPQGLPPS LQLLSLEANN I FSIRKENL ...String:
MVFPMWTLKR QILILFNIIL ISKLLGARWF PKTLPCDVTL DVPKNHVIVD CTDKHLTEIP GGIPTNTTNL TLTINHIPDI SPASFHRLD HLVEIDFRCN CVPIPLGSKN NMCIKRLQIK PRSFSGLTYL KSLYLDGNQL LEIPQGLPPS LQLLSLEANN I FSIRKENL TELANIEILY LGQNCYYRNP CYVSYSIEKD AFLNLTKLKV LSLKDNNVTA VPTVLPSTLT ELYLYNNMIA KI QEDDFNN LNQLQILDLS GNCPRCYNAP FPCAPCKNNS PLQIPVNAFD ALTELKVLRL HSNSLQHVPP RWFKNINKLQ ELD LSQNFL AKEIGDAKFL HFLPSLIQLD LSFNFELQVY RASMNLSQAF SSLKSLKILR IRGYVFKELK SFNLSPLHNL QNLE VLDLG TNFIKIANLS MFKQFKRLKV IDLSVNKISP SGDSSEVGFC SNARTSVESY EPQVLEQLHY FRYDKYARSC RFKNK EASF MSVNESCYKY GQTLDLSKNS IFFVKSSDFQ HLSFLKCLNL SGNLISQTLN GSEFQPLAEL RYLDFSNNRL DLLHST AFE ELHKLEVLDI SSNSHYFQSE GITHMLNFTK NLKVLQKLMM NDNDISSSTS RTMESESLRT LEFRGNHLDV LWREGDN RY LQLFKNLLKL EELDISKNSL SFLPSGVFDG MPPNLKNLSL AKNGLKSFSW KKLQCLKNLE TLDLSHNQLT TVPERLSN C SRSLKNLILK NNQIRSLTKY FLQDAFQLRY LDLSSNKIQM IQKTSFPENV LNNLKMLLLH HNRFLCTCDA VWFVWWVNH TEVTIPYLAT DVTCVGPGAH KGQSVISLDL YTCELDLTNL ILFSLSISVS LFLMVMMTAS HLYFWDVWYI YHFCKAKIKG YQRLISPDC CYDAFIVYDT KDPAVTEWVL AELVAKLEDP REKHFNLCLE ERDWLPGQPV LENLSQSIQL SKKTVFVMTD K YAKTENFK IAFYLSHQRL MDEKVDVIIL IFLEKPFQKS KFLQLRKRLC GSSVLEWPTN PQAHPYFWQC LKNALATDNH VA YSQVFKE TV

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Macromolecule #2: Protein unc-93 homolog B1

MacromoleculeName: Protein unc-93 homolog B1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 66.695969 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MEAEPPLYPM AGAAGPQGDE DLLGVPDGPE APLDELVGAY PNYNEEEEER RYYRRKRLGV LKNVLAASAG GMLTYGVYLG LLQMQLILH YDETYREVKY GNMGLPDIDS KMLMGINVTP IAALLYTPVL IRFFGTKWMM FLAVGIYALF VSTNYWERYY T LVPSAVAL ...String:
MEAEPPLYPM AGAAGPQGDE DLLGVPDGPE APLDELVGAY PNYNEEEEER RYYRRKRLGV LKNVLAASAG GMLTYGVYLG LLQMQLILH YDETYREVKY GNMGLPDIDS KMLMGINVTP IAALLYTPVL IRFFGTKWMM FLAVGIYALF VSTNYWERYY T LVPSAVAL GMAIVPLWAS MGNYITRMAQ KYHEYSHYKE QDGQGMKQRP PRGSHAPYLL VFQAIFYSFF HLSFACAQLP MI YFLNHYL YDLNHTLYNV QSCGTNSHGI LSGFNKTVLR TLPRSGNLIV VESVLMAVAF LAMLLVLGLC GAAYRPTEEI DLR SVGWGN IFQLPFKHVR DYRLRHLVPF FIYSGFEVLF ACTGIALGYG VCSVGLERLA YLLVAYSLGA SAASLLGLLG LWLP RPVPL VAGAGVHLLL TFILFFWAPV PRVLQHSWIL YVAAALWGVG SALNKTGLST LLGILYEDKE RQDFIFTIYH WWQAV AIFT VYLGSSLHMK AKLAVLLVTL VAAAVSYLRM EQKLRRGVAP RQPRIPRPQH KVRGYRYLEE DNSDESDAEG EHGDGA EEE APPAGPRPGP EPAGLGRRPC PYEQAQGGDG PEEQ

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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: 7.5
Details: 25 mM Hepes-NaOH, pH 7.5, 0.2 M NaCl, and 0.01% GDN
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 4.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 175000
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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