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- EMDB-34091: TLR7 in complex with an inhibitor -

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Basic information

Entry
Database: EMDB / ID: EMD-34091
TitleTLR7 in complex with an inhibitor
Map data
Sample
  • Complex: TLR7 in complex with an inhibitor
    • Protein or peptide: Toll-like receptor 7
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (2R,6R)-4-(8-cyanoquinolin-5-yl)-N-[(3S,4R)-4-fluoranylpyrrolidin-3-yl]-6-methyl-morpholine-2-carboxamide
KeywordsTLR7 / antagonist / IMMUNE SYSTEM
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 / cellular response to virus / positive regulation of interleukin-6 production / positive regulation of type II interferon production / cellular response to mechanical stimulus / double-stranded RNA binding / defense response to virus / positive regulation of canonical NF-kappaB signal transduction / lysosome / single-stranded RNA binding / 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: 2.77 Å
AuthorsZhang Z / Ohto U / Shimizu T
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Eur J Pharmacol / Year: 2023
Title: A novel Toll-like receptor 7/8-specific antagonist E6742 ameliorates clinically relevant disease parameters in murine models of lupus.
Authors: Sally T Ishizaka / Lynn Hawkins / Qian Chen / Fumitoshi Tago / Takuya Yagi / Kentaro Sakaniwa / Zhikuan Zhang / Toshiyuki Shimizu / Manabu Shirato /
Abstract: The sensing of self RNA by the endosomal Toll-like receptors (TLRs) 7 and 8 initiates pathogenic mechanisms underlying the autoimmune disease lupus. A blockade of the TLR7/8 signals may, therefore, ...The sensing of self RNA by the endosomal Toll-like receptors (TLRs) 7 and 8 initiates pathogenic mechanisms underlying the autoimmune disease lupus. A blockade of the TLR7/8 signals may, therefore, be a novel therapeutic intervention for lupus. To test the hypothesis, a novel compound E6742 that blocks TLR7/8 activation was identified. The mode of action of E6742 was investigated by analysis of the tertiary structure of TLR7 and 8 in complex with E6742. The in vitro activities of the compound were examined in cellular systems and its therapeutic potential was evaluated in murine lupus models. Tertiary structures of the extracellular domain of TLR7 and 8 in complex with E6742 showed that E6742 binds specifically and non-covalently to the hydrophobic pocket located at the interface of TLR7 or TLR8 homodimers. E6742 potently and selectively inhibited several TLR7/8-mediated cytokine responses in human PBMC. In two mouse models of lupus, oral dosing of E6742 after the onset of disease suppressed increase in autoantibodies and blocked the advance of organ damage. Collectively, the data show that TLR7/8 activation contributes to disease progression and its blocking by E6742 has potential as a therapeutic intervention for lupus.
History
DepositionAug 15, 2022-
Header (metadata) releaseNov 15, 2023-
Map releaseNov 15, 2023-
UpdateDec 4, 2024-
Current statusDec 4, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_34091.png

Downloads & links

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Map

FileDownload / File: emd_34091.map.gz / Format: CCP4 / Size: 15.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.25 Å/pix.
x 160 pix.
= 199.2 Å		1.25 Å/pix.
x 160 pix.
= 199.2 Å		1.25 Å/pix.
x 160 pix.
= 199.2 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.245 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.06
Minimum - Maximum-0.269882 - 0.40243375
Average (Standard dev.)0.00010288662 (±0.016879184)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions160160160
Spacing160160160
CellA=B=C: 199.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Unsharpened map

Fileemd_34091_additional_1.map
AnnotationUnsharpened map
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Half map: #2

Fileemd_34091_half_map_1.map
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Half map: #1

Fileemd_34091_half_map_2.map
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Sample components

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Entire : TLR7 in complex with an inhibitor

EntireName: TLR7 in complex with an inhibitor
Components
  • Complex: TLR7 in complex with an inhibitor
    • Protein or peptide: Toll-like receptor 7
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (2R,6R)-4-(8-cyanoquinolin-5-yl)-N-[(3S,4R)-4-fluoranylpyrrolidin-3-yl]-6-methyl-morpholine-2-carboxamide

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Supramolecule #1: TLR7 in complex with an inhibitor

SupramoleculeName: TLR7 in complex with an inhibitor / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Macaca mulatta (Rhesus monkey)
Molecular weightTheoretical: 200 KDa

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Macromolecule #1: Toll-like receptor 7

MacromoleculeName: Toll-like receptor 7 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Macaca mulatta (Rhesus monkey)
Molecular weightTheoretical: 111.561273 KDa
Recombinant expressionOrganism: Drosophila melanogaster (fruit fly)
SequenceString: MKLCILLAVV AFVGLSLGRS PWARWFPKTL PCDVTLDVSK NHVIVDCTDK HLTEIPGGIP TNTTNLTLTI NHIPDISPAS FHRLVHLVE IDFRCNCVPI RLGSKSNMCP RRLQIKPRSF SGLTYLKSLY LDGNQLLEIP QGLPPSLQLL SLEANNIFSI R KEQLTELA ...String:
MKLCILLAVV AFVGLSLGRS PWARWFPKTL PCDVTLDVSK NHVIVDCTDK HLTEIPGGIP TNTTNLTLTI NHIPDISPAS FHRLVHLVE IDFRCNCVPI RLGSKSNMCP RRLQIKPRSF SGLTYLKSLY LDGNQLLEIP QGLPPSLQLL SLEANNIFSI R KEQLTELA NIEILYLGQN CYYRNPCYVS YSIEKDAFLN LTKLKVLSLK DNNVTTVPTV LPSTLTELYL YNNMIAEIQE DD FNNLNQL QILDLSGNCP RCYNAPFPCT PCKNNSPLQI PVNAFDALTE LKVLRLHSNS LQHVPPRWFK NINNLQELDL SQN FLAKEI GDAKFLHFLP NLIQLDLSFN FELQVYRASM NLSQAFSSLK SLKILRIRGY VFKELKSFQL SPLHNLQNLE VLDL GTNFI KIANLSMFKQ FKRLKVIDLS VNKISPSGDS LVPRGSSNAR TSVESYEPQV LEQLYYFRYD KYARSCRFKN KEASF TSVQ ESCYKYGQTL DLSKNSIFFI KSSDFQHLSF LKCLNLSGNL ISQTLNGSEF QPLAELRYLD FSNNRLDLLH STAFEE LRK LEVLDISSNS HYFQSEGITH MLNFTKNLKV LQKLMMNDND ISSSTSRTME SESLRTLEFR GNHLDVLWRD GDNRYLQ LF KNLLKLEELD ISKNSLSFLP SGVFDGMPPN LKNLSLAKNG LKSFIWEKLR YLKNLETLDL SHNQLTTVPE RLSNCSRS L KNLILKNNQI RSLTKYFLQD AFQLRYLDLS SNKIQMIQKT SFPENVLNNL KMLLLHHNRF LCTCDAVWFV WWVQHTEVT IPYLATDVTC VGPGAHKGQS VISLDLYTCE LDLTNEFLVP RGSAAQHDEA VDNKFNKEQQ NAFYEILHLP NLNEEQRNAF IQSLKDDPS QSANLLAEAK KLNDAQAPKV DNKFNKEQQN AFYEILHLPN LNEEQRNAFI QSLKDDPSQS ANLLAEAKKL N DAQAPKVD ANSSSVP

UniProtKB: Toll-like receptor 7

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 10 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

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Macromolecule #4: (2R,6R)-4-(8-cyanoquinolin-5-yl)-N-[(3S,4R)-4-fluoranylpyrrolidin...

MacromoleculeName: (2R,6R)-4-(8-cyanoquinolin-5-yl)-N-[(3S,4R)-4-fluoranylpyrrolidin-3-yl]-6-methyl-morpholine-2-carboxamide
type: ligand / ID: 4 / Number of copies: 2 / Formula: JRI
Molecular weightTheoretical: 383.419 Da
Chemical component information

ChemComp-JRI:
(2R,6R)-4-(8-cyanoquinolin-5-yl)-N-[(3S,4R)-4-fluoranylpyrrolidin-3-yl]-6-methyl-morpholine-2-carboxamide

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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

Concentration0.8 mg/mL
BufferpH: 4.8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Detector mode: COUNTING / Average electron dose: 61.1 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.77 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1.1) / Number images used: 91789
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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