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- EMDB-30293: Cryo-EM structure of human TLR3 in complex with UNC93B1 -

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Basic information

Entry
Database: EMDB / ID: EMD-30293
TitleCryo-EM structure of human TLR3 in complex with UNC93B1
Map data
Sample
  • Complex: Complex of TLR3 and UNC93B1
    • Protein or peptide: Toll-like receptor 3
    • Protein or peptide: Protein unc-93 homolog B1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information


TLR3 deficiency - HSE / UNC93B1 deficiency - HSE / TICAM1 deficiency - HSE / type III interferon production / positive regulation of type III interferon production / response to dsRNA / TRAF3 deficiency - HSE / toll-like receptor 7 signaling pathway / T cell antigen processing and presentation / regulation of dendritic cell cytokine production ...TLR3 deficiency - HSE / UNC93B1 deficiency - HSE / TICAM1 deficiency - HSE / type III interferon production / positive regulation of type III interferon production / response to dsRNA / TRAF3 deficiency - HSE / toll-like receptor 7 signaling pathway / T cell antigen processing and presentation / regulation of dendritic cell cytokine production / Toll Like Receptor 3 (TLR3) Cascade / TLR3-mediated TICAM1-dependent programmed cell death / I-kappaB phosphorylation / inflammatory response to wounding / Toll-like receptor binding / toll-like receptor 3 signaling pathway / detection of virus / necroptotic signaling pathway / toll-like receptor 9 signaling pathway / activation of NF-kappaB-inducing kinase activity / RIP-mediated NFkB activation via ZBP1 / positive regulation of cytokine production involved in inflammatory response / early phagosome / endolysosome membrane / hyperosmotic response / Trafficking and processing of endosomal TLR / positive regulation of macrophage cytokine production / pattern recognition receptor activity / toll-like receptor signaling pathway / response to exogenous dsRNA / cellular response to exogenous dsRNA / negative regulation of osteoclast differentiation / positive regulation of interferon-alpha production / cellular response to interferon-beta / extrinsic apoptotic signaling pathway / positive regulation of chemokine production / JNK cascade / TICAM1,TRAF6-dependent induction of TAK1 complex / TICAM1-dependent activation of IRF3/IRF7 / extracellular matrix / positive regulation of interferon-beta production / positive regulation of interleukin-12 production / TICAM1, RIP1-mediated IKK complex recruitment / positive regulation of interleukin-8 production / microglial cell activation / positive regulation of JNK cascade / intracellular protein transport / cell morphogenesis / cellular response to virus / positive regulation of inflammatory response / cellular response to type II interferon / positive regulation of interleukin-6 production / positive regulation of non-canonical NF-kappaB signal transduction / cellular response to mechanical stimulus / male gonad development / positive regulation of angiogenesis / antigen processing and presentation of exogenous peptide antigen via MHC class II / transmembrane signaling receptor activity / positive regulation of type II interferon production / cellular response to xenobiotic stimulus / double-stranded RNA binding / positive regulation of tumor necrosis factor production / signaling receptor activity / defense response to virus / positive regulation of canonical NF-kappaB signal transduction / lysosome / early endosome / endosome membrane / endosome / defense response to bacterium / positive regulation of apoptotic process / lysosomal membrane / Golgi membrane / innate immune response / endoplasmic reticulum membrane / positive regulation of gene expression / endoplasmic reticulum / signal transduction / positive regulation of transcription by RNA polymerase II / extracellular space / membrane / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
Protein unc-93 homolog B1 / Toll-like receptor 3 trans-membrane domain / Toll-like receptor 3 trans-membrane domain / Toll-like receptor / Leucine Rich repeat / TIR domain / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Toll - interleukin 1 - resistance / Leucine-rich repeat, SDS22-like subfamily ...Protein unc-93 homolog B1 / Toll-like receptor 3 trans-membrane domain / Toll-like receptor 3 trans-membrane domain / Toll-like receptor / Leucine Rich repeat / TIR domain / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Toll - interleukin 1 - resistance / Leucine-rich repeat, SDS22-like subfamily / 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
Toll-like receptor 3 / Protein unc-93 homolog B1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 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
DepositionMay 23, 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: 0.01
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.01
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  • Surface view with fitted model
  • Atomic models: PDB-7c76
  • Surface level: 0.01
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30293.png

Downloads & links

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Map

FileDownload / File: emd_30293.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: 0.01 / Movie #1: 0.01
Minimum - Maximum-0.05652513 - 0.08478708
Average (Standard dev.)-6.4713913e-07 (±0.002289599)
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-0.0570.085-0.000

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Supplemental data

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Sample components

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Entire : Complex of TLR3 and UNC93B1

EntireName: Complex of TLR3 and UNC93B1
Components
  • Complex: Complex of TLR3 and UNC93B1
    • Protein or peptide: Toll-like receptor 3
    • Protein or peptide: Protein unc-93 homolog B1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Complex of TLR3 and UNC93B1

SupramoleculeName: Complex of TLR3 and UNC93B1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: Expi293F

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Macromolecule #1: Toll-like receptor 3

MacromoleculeName: Toll-like receptor 3 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 103.94632 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MRQTLPCIYF WGGLLPFGML CASSTTKCTV SHEVADCSHL KLTQVPDDLP TNITVLNLTH NQLRRLPAAN FTRYSQLTSL DVGFNTISK LEPELCQKLP MLKVLNLQHN ELSQLSDKTF AFCTNLTELH LMSNSIQKIK NNPFVKQKNL ITLDLSHNGL S STKLGTQV ...String:
MRQTLPCIYF WGGLLPFGML CASSTTKCTV SHEVADCSHL KLTQVPDDLP TNITVLNLTH NQLRRLPAAN FTRYSQLTSL DVGFNTISK LEPELCQKLP MLKVLNLQHN ELSQLSDKTF AFCTNLTELH LMSNSIQKIK NNPFVKQKNL ITLDLSHNGL S STKLGTQV QLENLQELLL SNNKIQALKS EELDIFANSS LKKLELSSNQ IKEFSPGCFH AIGRLFGLFL NNVQLGPSLT EK LCLELAN TSIRNLSLSN SQLSTTSNTT FLGLKWTNLT MLDLSYNNLN VVGNDSFAWL PQLEYFFLEY NNIQHLFSHS LHG LFNVRY LNLKRSFTKQ SISLASLPKI DDFSFQWLKC LEHLNMEDND IPGIKSNMFT GLINLKYLSL SNSFTSLRTL TNET FVSLA HSPLHILNLT KNKISKIESD AFSWLGHLEV LDLGLNEIGQ ELTGQEWRGL ENIFEIYLSY NKYLQLTRNS FALVP SLQR LMLRRVALKN VDSSPSPFQP LRNLTILDLS NNNIANINDD MLEGLEKLEI LDLQHNNLAR LWKHANPGGP IYFLKG LSH LHILNLESNG FDEIPVEVFK DLFELKIIDL GLNNLNTLPA SVFNNQVSLK SLNLQKNLIT SVEKKVFGPA FRNLTEL DM RFNPFDCTCE SIAWFVNWIN ETHTNIPELS SHYLCNTPPH YHGFPVRLFD TSSCKDSAPF ELFFMINTSI LLIFIFIV L LIHFEGWRIS FYWNVSVHRV LGFKEIDRQT EQFEYAAYII HAYKDKDWVW EHFSSMEKED QSLKFCLEER DFEAGVFEL EAIVNSIKRS RKIIFVITHH LLKDPLCKRF KVHHAVQQAI EQNLDSIILV FLEEIPDYKL NHALCLRRGM FKSHCILNWP VQKERIGAF RHKLQVALGS KNSVH

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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: 1 / 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 #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 9 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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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: 5.5
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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

1ziw

Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 134000

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