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Structure paper

TitleStructural analysis reveals TLR7 dynamics underlying antagonism.
Journal, issue, pagesNat Commun, Vol. 11, Issue 1, Page 5204, Year 2020
Publish dateOct 15, 2020
AuthorsShingo 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 /
PubMed AbstractToll-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.
External linksNat Commun / PubMed:33060576 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.6 - 4.4 Å
Structure data

EMDB-0999:
Cryo-EM reconstruction of TLR7/Cpd-3 (SM-394830) complex in closed form
Method: EM (single particle) / Resolution: 4.1 Å

EMDB-1000:
Cryo-EM reconstruction of TLR7/Cpd-6 (DSR-139293) complex in closed form
Method: EM (single particle) / Resolution: 4.4 Å

EMDB-30000:
Cryo-EM reconstruction of TLR7/Cpd-6 (DSR-139293) complex in open form
Method: EM (single particle) / Resolution: 4.4 Å

EMDB-30001:
Cryo-EM reconstruction of TLR7/Cpd-7 (DSR-139970) complex in open form
Method: EM (single particle) / Resolution: 4.1 Å

30002

6lw1

EMDB-30002, PDB-6lw1:
Cryo-EM structure of TLR7/Cpd-7 (DSR-139970) complex in open form
Method: EM (single particle) / Resolution: 2.8 Å

PDB-6lvx:
Crystal structure of TLR7/Cpd-1 (SM-374527) complex
Method: X-RAY DIFFRACTION / Resolution: 2.77 Å

PDB-6lvy:
Crystal structure of TLR7/Cpd-2 (SM-360320) complex
Method: X-RAY DIFFRACTION / Resolution: 2.6 Å

PDB-6lvz:
Crystal structure of TLR7/Cpd-3 (SM-394830) complex
Method: X-RAY DIFFRACTION / Resolution: 2.83 Å

PDB-6lw0:
Crystal structure of TLR7/Cpd-6 (DSR-139293) complex
Method: X-RAY DIFFRACTION / Resolution: 2.6 Å

Chemicals

ChemComp-EWL:
6-azanyl-2-butoxy-9-(phenylmethyl)-7H-purin-8-one

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

ChemComp-SO4:
SULFATE ION

ChemComp-HOH:
WATER

ChemComp-EWU:
6-azanyl-2-(2-methoxyethoxy)-9-(phenylmethyl)-7H-purin-8-one

ChemComp-EWX:
6-azanyl-2-(2-methoxyethoxy)-9-(pyridin-3-ylmethyl)-7H-purin-8-one

ChemComp-EX0:
2-ethoxy-8-(5-fluoranylpyridin-3-yl)-9-[[4-[[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]methyl]phenyl]methyl]purin-6-amine

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

Source
  • macaca mulatta (Rhesus monkey)
KeywordsIMMUNE SYSTEM / TLR7 / agonist / antagonist

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