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- PDB-6lvy: Crystal structure of TLR7/Cpd-2 (SM-360320) complex -

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Basic information

Entry
Database: PDB / ID: 6lvy
TitleCrystal structure of TLR7/Cpd-2 (SM-360320) complex
ComponentsToll-like receptor 7
KeywordsIMMUNE SYSTEM / TLR7 / agonist
Function / homology
Function and homology information


toll-like receptor 7 signaling pathway / response to cGMP / siRNA binding / early phagosome / positive regulation of macrophage cytokine production / pattern recognition receptor activity / toll-like receptor signaling pathway / positive regulation of interferon-alpha production / canonical NF-kappaB signal transduction / positive regulation of chemokine production ...toll-like receptor 7 signaling pathway / response to cGMP / siRNA binding / early phagosome / positive regulation of macrophage cytokine production / pattern recognition receptor activity / toll-like receptor signaling pathway / 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 / regulation of protein phosphorylation / cellular response to virus / positive regulation of interleukin-6 production / positive regulation of non-canonical NF-kappaB signal transduction / cellular response to mechanical stimulus / positive regulation of type II interferon production / double-stranded RNA binding / defense response to virus / lysosome / single-stranded RNA binding / receptor complex / endosome / inflammatory response / innate immune response / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / plasma membrane
Similarity search - Function
TIR domain / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Toll - interleukin 1 - resistance / Leucine-rich repeat, SDS22-like subfamily / TIR domain profile. / 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 / Leucine-rich repeat, SDS22-like subfamily / TIR domain profile. / 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
Chem-EWU / Toll-like receptor 7
Similarity search - Component
Biological speciesMacaca mulatta (Rhesus monkey)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 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 1.1Nov 29, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)194,14326
Polymers189,4912
Non-polymers4,65224
Water1,33374
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11450 Å2
ΔGint-105 kcal/mol
Surface area63330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.002, 138.369, 148.649
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 0 / Ens-ID: 1 / Beg auth comp-ID: ALA / Beg label comp-ID: ALA / End auth comp-ID: LEU / End label comp-ID: LEU / Refine code: 0 / Auth seq-ID: 27 - 835 / Label seq-ID: 5 - 813

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

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Protein , 1 types, 2 molecules AB

#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

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Sugars , 2 types, 12 molecules

#2: 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-Glycam 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
[]{[(4+1)][b-D-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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 10
Source method: isolated from a genetically manipulated source
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

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Non-polymers , 3 types, 86 molecules

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


Mass: 315.327 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H17N5O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 74 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.69 Å3/Da / Density % sol: 54.22 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: PEG 3350 or PEG 8000, ammonium sulfate, sodium citrate pH 5.0, Tris-HCl pH 7.5, NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-5A / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 2M / Detector: PIXEL / Date: Nov 18, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→50.01 Å / Num. obs: 63518 / % possible obs: 100 % / Redundancy: 13.4 % / CC1/2: 0.999 / Net I/σ(I): 20.8
Reflection shellResolution: 2.6→2.66 Å / Num. unique obs: 4417 / CC1/2: 0.779

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Processing

Software
NameVersionClassification
REFMAC5.8.0103refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5GMH

5gmh


Resolution: 2.6→50.01 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.915 / SU B: 11.097 / SU ML: 0.229 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.612 / ESU R Free: 0.292
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2393 3048 4.8 %RANDOM
Rwork0.1944 ---
obs0.1966 60395 99.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 163.99 Å2 / Biso mean: 48.455 Å2 / Biso min: 19.41 Å2
Baniso -1Baniso -2Baniso -3
1-0.32 Å2-0 Å2-0 Å2
2---0.82 Å20 Å2
3---0.5 Å2
Refinement stepCycle: final / Resolution: 2.6→50.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12473 0 292 74 12839
Biso mean--61.72 34.95 -
Num. residues----1542
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.01913051
X-RAY DIFFRACTIONr_bond_other_d0.0050.0212526
X-RAY DIFFRACTIONr_angle_refined_deg1.6831.99717708
X-RAY DIFFRACTIONr_angle_other_deg1.105328832
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.90651534
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.0224.714594
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.84152320
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.3661564
X-RAY DIFFRACTIONr_chiral_restr0.0890.22049
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.02114402
X-RAY DIFFRACTIONr_gen_planes_other0.0040.022994
Refine LS restraints NCS

Ens-ID: 1 / Number: 103420 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.03 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.6→2.667 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.354 199 -
Rwork0.306 4416 -
all-4615 -
obs--100 %

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