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- PDB-7cyn: Cryo-EM structure of human TLR7 in complex with UNC93B1 -

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Basic information

Entry
Database: PDB / ID: 7cyn
TitleCryo-EM structure of human TLR7 in complex with UNC93B1
Components
  • Protein unc-93 homolog B1
  • Toll-like receptor 7
KeywordsIMMUNE SYSTEM / Toll-like receptors / UNC93B1 / MFS
Function / homology
Function and homology information


Defective regulation of TLR7 by endogenous ligand / UNC93B1 deficiency - HSE / Toll Like Receptor 7/8 (TLR7/8) Cascade / toll-like receptor 7 signaling pathway / T cell antigen processing and presentation / toll-like receptor 8 signaling pathway / I-kappaB phosphorylation / MyD88 dependent cascade initiated on endosome / TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation / response to cGMP ...Defective regulation of TLR7 by endogenous ligand / UNC93B1 deficiency - HSE / Toll Like Receptor 7/8 (TLR7/8) Cascade / toll-like receptor 7 signaling pathway / T cell antigen processing and presentation / toll-like receptor 8 signaling pathway / I-kappaB phosphorylation / MyD88 dependent cascade initiated on endosome / TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation / response to cGMP / Toll-like receptor binding / toll-like receptor 3 signaling pathway / Regulation of TLR by endogenous ligand / toll-like receptor 9 signaling pathway / siRNA binding / early phagosome / endolysosome membrane / Trafficking and processing of endosomal TLR / positive regulation of macrophage cytokine production / toll-like receptor signaling pathway / pattern recognition receptor activity / RSV-host interactions / positive regulation of interferon-alpha production / canonical NF-kappaB signal transduction / positive regulation of chemokine production / JNK cascade / positive regulation of interleukin-12 production / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / positive regulation of interferon-beta production / positive regulation of interleukin-8 production / intracellular protein transport / positive regulation of non-canonical NF-kappaB signal transduction / cell morphogenesis / antigen processing and presentation of exogenous peptide antigen via MHC class II / positive regulation of interleukin-6 production / cellular response to virus / cellular response to mechanical stimulus / positive regulation of inflammatory response / positive regulation of type II interferon production / SARS-CoV-1 activates/modulates innate immune responses / double-stranded RNA binding / positive regulation of canonical NF-kappaB signal transduction / defense response to virus / Potential therapeutics for SARS / single-stranded RNA binding / lysosome / receptor complex / endosome / endosome membrane / inflammatory response / Golgi membrane / innate immune response / endoplasmic reticulum membrane / SARS-CoV-2 activates/modulates innate and adaptive immune responses / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / plasma membrane / cytoplasm
Similarity search - Function
Ion channel regulatory protein UNC-93 / Protein unc-93 homolog B1 / TIR domain / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Leucine Rich Repeat / Toll - interleukin 1 - resistance / TIR domain profile. / Leucine-rich repeat, SDS22-like subfamily / Toll/interleukin-1 receptor homology (TIR) domain ...Ion channel regulatory protein UNC-93 / Protein unc-93 homolog B1 / TIR domain / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Leucine Rich Repeat / Toll - interleukin 1 - resistance / TIR domain profile. / Leucine-rich repeat, SDS22-like subfamily / 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)
MethodELECTRON MICROSCOPY / single 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, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 6, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 27, 2021Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Feb 24, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 23, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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Assembly

Deposited unit
A: Toll-like receptor 7
B: Toll-like receptor 7
C: Protein unc-93 homolog B1
D: Protein unc-93 homolog B1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)376,8048
Polymers375,5134
Non-polymers1,2914
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Toll-like receptor 7


Mass: 121060.586 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TLR7, UNQ248/PRO285 / Cell line (production host): Expi293F / Production host: Homo sapiens (human) / References: UniProt: Q9NYK1
#2: Protein Protein unc-93 homolog B1 / hUNC93B1


Mass: 66695.969 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UNC93B1, UNC93, UNC93B / Cell line (production host): Expi293F / Production host: Homo sapiens (human) / References: UniProt: Q9H1C4
#3: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestN
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

ComponentName: Complex of TLR7 and UNC93B1 / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
Details: 25 mM Hepes-NaOH, pH 7.5, 0.2 M NaCl, and 0.01% GDN
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 4.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 175000 / Symmetry type: POINT

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