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- PDB-9mhy: Human TLR8 ectodomain with small molecule agonist 1 -

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Basic information

Entry
Database: PDB / ID: 9mhy
TitleHuman TLR8 ectodomain with small molecule agonist 1
ComponentsToll-like receptor 8
KeywordsIMMUNE SYSTEM / Toll-like receptor 8 / agonist
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 / toll-like receptor signaling pathway / pattern recognition receptor activity / 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 / toll-like receptor signaling pathway / pattern recognition receptor activity / 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 / 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 / signaling receptor activity / defense response to virus / positive regulation of canonical NF-kappaB signal transduction / single-stranded RNA binding / endosome membrane / inflammatory response / Golgi membrane / external side of plasma 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 / 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 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.66 Å
AuthorsCritton, D.A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2025
Title: Structure-Based Design of Novel TLR7/8 Agonist Payloads Enabling an Immunomodulatory Conjugate Approach.
Authors: Poudel, Y.B. / Lo, J.C. / Norris, D.J. / Cox, M. / He, L. / Johnson, W.L. / A M Subbaiah, M. / Mondal, S. / Thangavel, S. / Subramani, L. / Reddy, M. / Jain, S. / Weiss, D.R. / Sivaprakasam, ...Authors: Poudel, Y.B. / Lo, J.C. / Norris, D.J. / Cox, M. / He, L. / Johnson, W.L. / A M Subbaiah, M. / Mondal, S. / Thangavel, S. / Subramani, L. / Reddy, M. / Jain, S. / Weiss, D.R. / Sivaprakasam, P. / Critton, D. / Mulligan, D. / Xie, C. / Dhar, P. / Li, Y. / Sega, E. / Yamazoe, S. / Gavai, A.V. / Mathur, A. / Zapf, C.W. / Chekler, E.P.
History
DepositionDec 12, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 5, 2025Provider: repository / Type: Initial release

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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)194,02431
Polymers184,6162
Non-polymers9,40929
Water19,4381079
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)72.580, 82.410, 83.440
Angle α, β, γ (deg.)116.05, 97.71, 98.68
Int Tables number1
Space group name H-MP1

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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 / Fragment: residues 27-827
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, 24 molecules

#2: Polysaccharide alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(2-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(2-6)]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.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa2-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+2)][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.: 4
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 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


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 18
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, 1084 molecules

#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-A1BLN / (3S,4R)-4-[({3-[(5-amino-7-{[(3S)-1-hydroxyhexan-3-yl]amino}-1H-pyrazolo[4,3-d]pyrimidin-1-yl)methyl]-4-methoxyphenyl}methyl)amino]oxolan-3-ol


Mass: 485.579 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H35N7O4 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1079 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.34 Å3/Da / Density % sol: 47.41 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: 0.2 M magnesium formate, 20% (w/v) PEG 3,350, 0.1 M TCEP

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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 EIGER2 X 9M / Detector: PIXEL / Date: Nov 11, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.66→73.03 Å / Num. obs: 202912 / % possible obs: 81.1 % / Redundancy: 1.8 % / CC1/2: 0.999 / Net I/σ(I): 13.9
Reflection shellResolution: 1.66→1.83 Å / Mean I/σ(I) obs: 1.7 / Num. unique obs: 10634 / CC1/2: 0.615

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Processing

Software
NameVersionClassification
XDSdata reduction
XDSdata scaling
PHASERphasing
BUSTER2.11.7 (20-MAY-2020)refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.66→73.03 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.931 / SU R Cruickshank DPI: 0.37 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.18 / SU Rfree Blow DPI: 0.146 / SU Rfree Cruickshank DPI: 0.147
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION.
RfactorNum. reflection% reflectionSelection details
Rfree0.223 6152 5.08 %RANDOM
Rwork0.201 ---
obs0.202 121156 61.3 %-
Displacement parametersBiso mean: 37.15 Å2
Baniso -1Baniso -2Baniso -3
1--0.6744 Å2-0.602 Å20.1985 Å2
2--1.9343 Å20.1217 Å2
3----1.2599 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: LAST / Resolution: 1.66→73.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12023 0 615 1079 13717
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00825642HARMONIC2
X-RAY DIFFRACTIONt_angle_deg146415HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d7868SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes4086HARMONIC5
X-RAY DIFFRACTIONt_it13014HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.47
X-RAY DIFFRACTIONt_other_torsion14.92
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1816SEMIHARMONIC5
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_contact19779SEMIHARMONIC4
LS refinement shellResolution: 1.66→1.75 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.2565 129 5.32 %
Rwork0.229 2295 -
all0.2305 2424 -
obs--8.16 %
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)
10.42710.12-0.18750.3426-0.07790.6681-0.04510.00010.04780.01620.06010.0915-0.0771-0.1034-0.015-0.08420.0293-0.0197-0.04060.0206-0.044326.89166.3467-30.5878
20.47650.0627-0.23360.3272-0.11420.5404-0.0402-0.04060.02970.0260.072-0.025-0.0370.14-0.0318-0.0911-0.0235-0.02350.0111-0.0267-0.07864.918.6508-43.1961
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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