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- EMDB-1000: Cryo-EM reconstruction of TLR7/Cpd-6 (DSR-139293) complex in clos... -

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Basic information

Entry
Database: EMDB / ID: EMD-1000
TitleCryo-EM reconstruction of TLR7/Cpd-6 (DSR-139293) complex in closed form
Map data
Sample
  • Complex: TLR7/Cpd-6 (DSR-139293) complex
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 / 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 ...toll-like receptor 7 signaling pathway / toll-like receptor 8 signaling pathway / response to cGMP / siRNA binding / early phagosome / 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 / positive regulation of non-canonical NF-kappaB signal transduction / positive regulation of interleukin-6 production / cellular response to virus / cellular response to mechanical stimulus / positive regulation of type II interferon production / double-stranded RNA binding / positive regulation of canonical NF-kappaB signal transduction / defense response to virus / single-stranded RNA binding / lysosome / receptor complex / endosome / 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. / 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 ...TIR domain / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / 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
Toll-like receptor 7
Similarity search - Component
Biological speciesMacaca mulatta (Rhesus monkey)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.4 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, 2020-
Header (metadata) releaseNov 11, 2020-
Map releaseNov 11, 2020-
UpdateNov 11, 2020-
Current statusNov 11, 2020Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.026
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.026
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_1000.png

Downloads & links

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Map

FileDownload / File: emd_1000.map.gz / Format: CCP4 / Size: 18.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.34 Å/pix.
x 168 pix.
= 225.12 Å		1.34 Å/pix.
x 168 pix.
= 225.12 Å		1.34 Å/pix.
x 168 pix.
= 225.12 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.34 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.026 / Movie #1: 0.026
Minimum - Maximum-0.06154855 - 0.114882946
Average (Standard dev.)-0.00011738609 (±0.004912609)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions168168168
Spacing168168168
CellA=B=C: 225.12001 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.341.341.34
M x/y/z168168168
origin x/y/z0.0000.0000.000
length x/y/z225.120225.120225.120
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS168168168
D min/max/mean-0.0620.115-0.000

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Supplemental data

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Sample components

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Entire : TLR7/Cpd-6 (DSR-139293) complex

EntireName: TLR7/Cpd-6 (DSR-139293) complex
Components
  • Complex: TLR7/Cpd-6 (DSR-139293) complex

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Supramolecule #1: TLR7/Cpd-6 (DSR-139293) complex

SupramoleculeName: TLR7/Cpd-6 (DSR-139293) complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Macaca mulatta (Rhesus monkey)
Recombinant expressionOrganism: Drosophila melanogaster (fruit fly)
Molecular weightTheoretical: 200 KDa

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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

Concentration0.7 mg/mL
BufferpH: 4.8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD

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Image processing

Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 4.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 124485
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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