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- PDB-8s9h: Crystal structure of monkey TLR7 ectodomain with compound 14 -

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Basic information

Entry
Database: PDB / ID: 8s9h
TitleCrystal structure of monkey TLR7 ectodomain with compound 14
ComponentsToll-like receptor 7
KeywordsIMMUNE SYSTEM / Toll-like receptor 7 / pattern recognition receptor / agonist
Function / homology
Function and homology information


regulation of macromolecule metabolic process / inflammatory response / innate immune response / signal transduction / 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)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.437 Å
AuthorsCritton, D.A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2024
Title: Identification and Optimization of Small Molecule Pyrazolopyrimidine TLR7 Agonists for Applications in Immuno-oncology.
Authors: He, L. / Zhang, M.Y. / Cox, M. / Zhang, Q. / Donnell, A.F. / Zhang, Y. / Tarby, C. / Gill, P. / Subbaiah, M.A.M. / Ramar, T. / Reddy, M. / Puttapaka, V. / Li, Y.X. / Sivaprakasam, P. / ...Authors: He, L. / Zhang, M.Y. / Cox, M. / Zhang, Q. / Donnell, A.F. / Zhang, Y. / Tarby, C. / Gill, P. / Subbaiah, M.A.M. / Ramar, T. / Reddy, M. / Puttapaka, V. / Li, Y.X. / Sivaprakasam, P. / Critton, D. / Mulligan, D. / Xie, C. / Ramakrishnan, R. / Nagar, J. / Dudhgaonkar, S. / Murtaza, A. / Oderinde, M.S. / Schieven, G.L. / Mathur, A. / Gavai, A.V. / Vite, G. / Gangwar, S. / Poudel, Y.B.
History
DepositionMar 28, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 7, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)194,25524
Polymers188,0292
Non-polymers6,22622
Water12,809711
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11910 Å2
ΔGint38 kcal/mol
Surface area63350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)98.180, 138.880, 149.350
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Toll-like receptor 7


Mass: 94014.656 Da / Num. of mol.: 2
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: G8E2R2

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Sugars , 3 types, 18 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.: 1
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 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.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam 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
[][D-1-deoxy-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


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 14
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, 715 molecules

#5: Chemical ChemComp-ZWV / (3S)-3-{[5-amino-1-({3-methoxy-5-[1-(oxan-4-yl)piperidin-4-yl]pyridin-2-yl}methyl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl]amino}hexan-1-ol


Mass: 538.685 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H42N8O3 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 711 / 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: 2.71 Å3/Da / Density % sol: 54.57 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 5 / Details: 0.2 ammonium citrate pH 5.0, 20% (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 16, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.437→101.703 Å / Num. obs: 59766 / % possible obs: 94.7 % / Redundancy: 5.74 % / CC1/2: 0.991 / Net I/σ(I): 7.3
Reflection shellResolution: 2.437→2.681 Å / Num. unique obs: 2988 / CC1/2: 0.543

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (21-NOV-2022)refinement
autoPROCdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.437→35.32 Å / Cor.coef. Fo:Fc: 0.908 / Cor.coef. Fo:Fc free: 0.891 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.173 / SU Rfree Blow DPI: 0.338
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION.
RfactorNum. reflection% reflectionSelection details
Rfree0.2697 2884 4.83 %RANDOM
Rwork0.2466 ---
obs0.2477 59749 77.8 %-
Displacement parametersBiso mean: 53.24 Å2
Baniso -1Baniso -2Baniso -3
1--1.9135 Å20 Å20 Å2
2--1.1145 Å20 Å2
3---0.799 Å2
Refine analyzeLuzzati coordinate error obs: 0.41 Å
Refinement stepCycle: LAST / Resolution: 2.437→35.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12270 0 407 711 13388
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00725459HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9546048HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d7722SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes4063HARMONIC5
X-RAY DIFFRACTIONt_it12993HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.42
X-RAY DIFFRACTIONt_other_torsion15.32
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1770SEMIHARMONIC5
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_contact20129SEMIHARMONIC4
LS refinement shellResolution: 2.44→2.6 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.3191 -4.6 %
Rwork0.302 1140 -
all0.3027 1195 -
obs--9.02 %
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)
10.5028-0.078-0.3870.3190.06440.55230.0091-0.01320.0249-0.01360.0173-0.0360.0270.0306-0.0264-0.0617-0.0002-0.0351-0.01970.0021-0.050317.9141-1.7496-16.1789
20.63710.0932-0.30780.8822-0.08540.44910.03030.15640.0169-0.05470.01170.19420.0007-0.1414-0.0419-0.16030.0018-0.06090.0020.0049-0.0619-23.4906-1.7236-17.4853
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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