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- PDB-6lw1: Cryo-EM structure of TLR7/Cpd-7 (DSR-139970) complex in open form -

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Open data


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Basic information

Entry
Database: PDB / ID: 6lw1
TitleCryo-EM structure of TLR7/Cpd-7 (DSR-139970) complex in open form
ComponentsToll-like receptor 7
KeywordsIMMUNE SYSTEM / TLR7 / antagonist
Function / homology
Function and homology information


toll-like receptor 7 signaling pathway / toll-like receptor 8 signaling pathway / response to cGMP / siRNA binding / early phagosome / endolysosome membrane / positive regulation of macrophage cytokine production / toll-like receptor signaling pathway / pattern recognition receptor activity / positive regulation of interferon-alpha production ...toll-like receptor 7 signaling pathway / toll-like receptor 8 signaling pathway / response to cGMP / siRNA binding / early phagosome / endolysosome membrane / positive regulation of macrophage cytokine production / toll-like receptor signaling pathway / pattern recognition receptor activity / positive regulation of interferon-alpha production / canonical NF-kappaB signal transduction / positive regulation of chemokine production / JNK cascade / positive regulation of interferon-beta production / positive regulation of interleukin-8 production / cellular response to mechanical stimulus / cellular response to virus / positive regulation of interleukin-6 production / positive regulation of type II interferon production / positive regulation of inflammatory response / double-stranded RNA binding / defense response to virus / positive regulation of canonical NF-kappaB signal transduction / receptor complex / single-stranded RNA binding / inflammatory response / innate immune response / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / metal ion binding / plasma membrane
Similarity search - Function
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 / Leucine-rich repeat, SDS22-like subfamily / Toll/interleukin-1 receptor homology (TIR) domain superfamily / Leucine rich repeat / Leucine-rich repeat, typical subtype ...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 / Leucine-rich repeat, SDS22-like subfamily / 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
Chem-EX3 / Toll-like receptor 7
Similarity search - Component
Biological speciesMacaca mulatta (Rhesus monkey)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsZhang, Z. / Ohto, U. / Shimizu, T.
CitationJournal: Nat Commun / Year: 2020
Title: Structural analysis reveals TLR7 dynamics underlying antagonism.
Authors: Shingo Tojo / Zhikuan Zhang / Hiroyuki Matsui / Masahiro Tahara / Mitsunori Ikeguchi / Mami Kochi / Mami Kamada / Hideki Shigematsu / Akihisa Tsutsumi / Naruhiko Adachi / Takuma Shibata / ...Authors: Shingo Tojo / Zhikuan Zhang / Hiroyuki Matsui / Masahiro Tahara / Mitsunori Ikeguchi / Mami Kochi / Mami Kamada / Hideki Shigematsu / Akihisa Tsutsumi / Naruhiko Adachi / Takuma Shibata / Masaki Yamamoto / Masahide Kikkawa / Toshiya Senda / Yoshiaki Isobe / Umeharu Ohto / Toshiyuki Shimizu /
Abstract: Toll-like receptor 7 (TLR7) recognizes both microbial and endogenous RNAs and nucleosides. Aberrant activation of TLR7 has been implicated in several autoimmune diseases including systemic lupus ...Toll-like receptor 7 (TLR7) recognizes both microbial and endogenous RNAs and nucleosides. Aberrant activation of TLR7 has been implicated in several autoimmune diseases including systemic lupus erythematosus (SLE). Here, by modifying potent TLR7 agonists, we develop a series of TLR7-specific antagonists as promising therapeutic agents for SLE. These compounds protect mice against lethal autoimmunity. Combining crystallography and cryo-electron microscopy, we identify the open conformation of the receptor and reveal the structural equilibrium between open and closed conformations that underlies TLR7 antagonism, as well as the detailed mechanism by which TLR7-specific antagonists bind to their binding pocket in TLR7. Our work provides small-molecule TLR7-specific antagonists and suggests the TLR7-targeting strategy for treating autoimmune diseases.
History
DepositionFeb 6, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 11, 2020Provider: repository / Type: Initial release
Revision 1.0Nov 11, 2020Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Nov 11, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Nov 11, 2020Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Nov 11, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Nov 11, 2020Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Oct 30, 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
Revision 1.2Jul 2, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jul 2, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

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Assembly

Deposited unit
A: Toll-like receptor 7
B: Toll-like receptor 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)190,4664
Polymers189,4912
Non-polymers9752
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area2830 Å2
ΔGint-12 kcal/mol
Surface area62870 Å2

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Components

#1: Protein Toll-like receptor 7


Mass: 94745.594 Da / Num. of mol.: 2
Mutation: N145Q/N367Q/S418L/E419VV420P/G421R/F422G/C423S/N466Q/N777Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Macaca mulatta (Rhesus monkey) / Gene: TLR7 / Production host: Drosophila melanogaster (fruit fly) / References: UniProt: B3Y653
#2: Chemical ChemComp-EX3 / 2-ethoxy-8-(5-fluoranylpyridin-3-yl)-6-methyl-9-[[4-[[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]methyl]phenyl]methyl]purine


Mass: 487.572 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H30FN7O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
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: TLR7/Cpd-7 (DSR-139970) complex / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.2 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Macaca mulatta (Rhesus monkey)9544
21Staphylococcus aureus (bacteria)1280
Source (recombinant)Organism: Drosophila melanogaster (fruit fly)
Buffer solutionpH: 4.8
SpecimenConc.: 0.8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS 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

SoftwareName: PHENIX / Version: 1.17.1_3660: / Classification: refinement
EM software
IDNameVersionCategory
12RELION33D reconstruction
13PHENIXmodel refinement
CTF correctionType: NONE
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 301212 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00912678
ELECTRON MICROSCOPYf_angle_d0.93817188
ELECTRON MICROSCOPYf_dihedral_angle_d18.1331660
ELECTRON MICROSCOPYf_chiral_restr0.1291974
ELECTRON MICROSCOPYf_plane_restr0.0042180

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