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- PDB-7rc9: Crystal structure of human TLR8 ectodomain bound to small molecul... -

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Basic information

Entry
Database: PDB / ID: 7rc9
TitleCrystal structure of human TLR8 ectodomain bound to small molecule antagonist 21
ComponentsToll-like receptor 8
KeywordsRNA BINDING PROTEIN / Toll-like receptor / pattern recognition receptor / pathogen-associated molecular patterns / innate immunity / endosomal receptor
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 / immunoglobulin mediated immune response / positive regulation of interferon-alpha production ...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 / immunoglobulin mediated immune response / positive regulation of interferon-alpha production / 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 / cellular response to mechanical stimulus / positive regulation of interleukin-6 production / double-stranded RNA binding / positive regulation of type II interferon production / 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-RQY / Toll-like receptor 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.76 Å
AuthorsCritton, D.A.
CitationJournal: Acs Med.Chem.Lett. / Year: 2022
Title: Identification of 2-Pyridinylindole-Based Dual Antagonists of Toll-like Receptors 7 and 8 (TLR7/8).
Authors: Sreekantha, R.K. / Mussari, C.P. / Dodd, D.S. / Pasunoori, L. / Hegde, S. / Posy, S.L. / Critton, D. / Ruepp, S. / Subramanian, M. / Salter-Cid, L.M. / Tagore, D.M. / Sarodaya, S. / ...Authors: Sreekantha, R.K. / Mussari, C.P. / Dodd, D.S. / Pasunoori, L. / Hegde, S. / Posy, S.L. / Critton, D. / Ruepp, S. / Subramanian, M. / Salter-Cid, L.M. / Tagore, D.M. / Sarodaya, S. / Dudhgaonkar, S. / Poss, M.A. / Schieven, G.L. / Carter, P.H. / Macor, J.E. / Dyckman, A.J.
History
DepositionJul 7, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 4, 2022Provider: repository / Type: Initial release
Revision 1.1Jun 1, 2022Group: 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 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)194,11724
Polymers185,6712
Non-polymers8,44622
Water3,459192
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12980 Å2
ΔGint112 kcal/mol
Surface area60370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)160.889, 83.876, 153.524
Angle α, β, γ (deg.)90.000, 119.720, 90.000
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: 92835.367 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 , 4 types, 20 molecules

#2: 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-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#3: 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.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#4: Polysaccharide alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c3-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#5: 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.: 14 / Source method: obtained synthetically / 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, 194 molecules

#6: Chemical ChemComp-RQY / 2-(2,6-dimethylpyridin-4-yl)-5-(piperidin-4-yl)-3-(propan-2-yl)-1H-indole


Mass: 347.496 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H29N3 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 192 / 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: 2.42 Å3/Da / Density % sol: 49.23 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.2 M magnesium formate, 20% (w/v) PEG 3350, 10 mM spermine tetrahydrochloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 8, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.76→80.4 Å / Num. obs: 45471 / % possible obs: 99.5 % / Redundancy: 3.4 % / Biso Wilson estimate: 81.28 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.065 / Rpim(I) all: 0.041 / Rrim(I) all: 0.077 / Net I/σ(I): 12.8 / Num. measured all: 155231
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.76-2.913.50.542358266610.850.3350.6372.3100
8.74-80.43.40.028491714450.9990.0180.03338.295.5

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimless0.5.15data scaling
BUSTER2.11.6refinement
PDB_EXTRACT3.27data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3W3G

3w3g


Resolution: 2.76→40.41 Å / Cor.coef. Fo:Fc: 0.9158 / Cor.coef. Fo:Fc free: 0.9117 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.363
RfactorNum. reflection% reflectionSelection details
Rfree0.2618 2331 5.13 %RANDOM
Rwork0.2335 ---
obs0.235 45455 99 %-
Displacement parametersBiso max: 203.86 Å2 / Biso mean: 90.81 Å2 / Biso min: 38 Å2
Baniso -1Baniso -2Baniso -3
1-14.0118 Å20 Å21.7301 Å2
2---13.4041 Å20 Å2
3----0.6077 Å2
Refine analyzeLuzzati coordinate error obs: 0.462 Å
Refinement stepCycle: final / Resolution: 2.76→40.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11428 0 559 192 12179
Biso mean--101.66 60.78 -
Num. residues----1474
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d4233SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes301HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1770HARMONIC5
X-RAY DIFFRACTIONt_it12322HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1783SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact13199SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d12322HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg16879HARMONIC20.98
X-RAY DIFFRACTIONt_omega_torsion1.74
X-RAY DIFFRACTIONt_other_torsion18.47
LS refinement shellResolution: 2.76→2.83 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2668 165 5.21 %
Rwork0.2388 3000 -
all0.2403 3165 -
obs--93.9 %
Refinement TLS params.

Method: refined / 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)
13.5235-0.13250.32090.85460.18142.3095-0.1122-0.07150.1371-0.1437-0.0417-0.052-0.2785-0.05320.1539-0.1587-0.0246-0.0057-0.2695-0.0153-0.298428.3216-15.256429.4498
22.5923-0.2543-0.30911.59190.60442.1375-0.1776-0.2466-0.5617-0.03230.04420.37760.1625-0.58840.1334-0.1685-0.09980.04450.30910.2870.0819-5.13-36.608541.0073
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A32 - 818
2X-RAY DIFFRACTION2{ B|* }B32 - 818

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