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- PDB-6ty5: Crystal structure of human TLR8 in complex with Compound 11 -

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Basic information

Entry
Database: PDB / ID: 6ty5
TitleCrystal structure of human TLR8 in complex with Compound 11
ComponentsToll-like receptor 8
KeywordsIMMUNE SYSTEM / RNA recognition Leucine rich repeats Glycosylation Structure based drug design Immune System Innate immunity
Function / homology
Function and homology information


Toll Like Receptor 7/8 (TLR7/8) Cascade / toll-like receptor 8 signaling pathway / negative regulation of interleukin-12 production / endolysosome membrane / positive regulation of innate immune response / Trafficking and processing of endosomal TLR / pattern recognition receptor activity / toll-like receptor signaling pathway / positive regulation of interferon-alpha production / immunoglobulin mediated immune response ...Toll Like Receptor 7/8 (TLR7/8) Cascade / toll-like receptor 8 signaling pathway / negative regulation of interleukin-12 production / endolysosome membrane / positive regulation of innate immune response / Trafficking and processing of endosomal TLR / pattern recognition receptor activity / toll-like receptor signaling pathway / positive regulation of interferon-alpha production / immunoglobulin mediated immune response / canonical NF-kappaB signal transduction / positive regulation of interferon-beta production / positive regulation of interleukin-1 beta production / positive regulation of interleukin-8 production / regulation of protein phosphorylation / response to virus / positive regulation of interleukin-6 production / cellular response to mechanical stimulus / positive regulation of type II interferon production / double-stranded RNA binding / signaling receptor activity / defense response to virus / single-stranded RNA binding / endosome membrane / inflammatory response / external side of plasma membrane / Golgi membrane / innate immune response / endoplasmic reticulum membrane / SARS-CoV-2 activates/modulates innate and adaptive immune responses / DNA binding / RNA binding / identical protein binding / 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-O0W / Toll-like receptor 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.793 Å
AuthorsFaller, M. / Zink, F.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Target-Based Identification and Optimization of 5-Indazol-5-yl Pyridones as Toll-like Receptor 7 and 8 Antagonists Using a Biochemical TLR8 Antagonist Competition Assay.
Authors: Knoepfel, T. / Nimsgern, P. / Jacquier, S. / Bourrel, M. / Vangrevelinghe, E. / Glatthar, R. / Behnke, D. / Alper, P.B. / Michellys, P.Y. / Deane, J. / Junt, T. / Zipfel, G. / Limonta, S. / ...Authors: Knoepfel, T. / Nimsgern, P. / Jacquier, S. / Bourrel, M. / Vangrevelinghe, E. / Glatthar, R. / Behnke, D. / Alper, P.B. / Michellys, P.Y. / Deane, J. / Junt, T. / Zipfel, G. / Limonta, S. / Hawtin, S. / Andre, C. / Boulay, T. / Loetscher, P. / Faller, M. / Blank, J. / Feifel, R. / Betschart, C.
History
DepositionJan 15, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 12, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 26, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jan 24, 2024Group: 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Toll-like receptor 8
B: Toll-like receptor 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)192,81122
Polymers184,6162
Non-polymers8,19620
Water4,666259
1
A: Toll-like receptor 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)96,04310
Polymers92,3081
Non-polymers3,7359
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Toll-like receptor 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)96,76812
Polymers92,3081
Non-polymers4,46011
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)164.813, 87.722, 153.464
Angle α, β, γ (deg.)90, 120.46, 90
Int Tables number5
Space group name H-MC121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Toll-like receptor 8 /


Mass: 92307.766 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TLR8, UNQ249/PRO286 / Production host: Drosophila melanogaster (fruit fly) / References: UniProt: Q9NR97

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Sugars , 3 types, 18 molecules

#2: Polysaccharide
alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#3: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}}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.: 12
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 , 2 types, 261 molecules

#5: Chemical ChemComp-O0W / 5-methyl-7-(7-methyl-2-piperidin-4-yl-indazol-5-yl)furo[3,2-c]pyridin-4-one


Mass: 362.425 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H22N4O2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 259 / 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: 2.59 Å3/Da / Density % sol: 52.51 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop
Details: 20%(w/v) PEG3350, 0.2M Magnesium chloride hexahydrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9999 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 29, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.793→74.64 Å / Num. obs: 45252 / % possible obs: 96.02 % / Redundancy: 1.9 % / CC1/2: 1 / Net I/σ(I): 14.97
Reflection shellResolution: 2.793→2.893 Å / Num. unique obs: 4683 / CC1/2: 0.876

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (3-OCT-2019)refinement
Cootmodel building
PHASERphasing
XDSdata processing
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3W3G

3w3g


Resolution: 2.793→74.64 Å / Cor.coef. Fo:Fc: 0.907 / Cor.coef. Fo:Fc free: 0.892 / Cross valid method: THROUGHOUT / SU Rfree Blow DPI: 0.381
RfactorNum. reflection% reflectionSelection details
Rfree0.2641 2315 -RANDOM
Rwork0.2367 ---
obs0.2382 45216 96.1 %-
Displacement parametersBiso mean: 79.47 Å2
Baniso -1Baniso -2Baniso -3
1--5.6796 Å20 Å21.9498 Å2
2---14.794 Å20 Å2
3---20.4736 Å2
Refine analyzeLuzzati coordinate error obs: 0.45 Å
Refinement stepCycle: LAST / Resolution: 2.793→74.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11723 0 544 269 12536
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00412557HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.7317132HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d4440SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes2105HARMONIC5
X-RAY DIFFRACTIONt_it12557HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion1783SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact8448SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion1.92
X-RAY DIFFRACTIONt_other_torsion15.73
LS refinement shellResolution: 2.793→3 Å
RfactorNum. reflection% reflection
Rfree0.2568 33 -
Rwork0.2397 --
obs--99.89 %
Refinement TLS params.

Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.4581-0.0848-0.12770.3376-0.08760.38780.0025-0.0004-0.0072-0.00040.0007-0.0085-0.0072-0.0085-0.00330.0001-0.0019-0.00280.00220.0061-0.005414.5972-2.334937.6029
20.2205-0.01660.01150.53510.13690.4167-0.0018-0.00240.0059-0.00240.00470.00940.00590.0094-0.00290.0002-0.00750.0025-0.00270.00240.000850.7909-22.991225.1842
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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