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- PDB-9hcl: Crystal structure of human TRF1 TRFH domain in complex with compo... -

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Basic information

Entry
Database: PDB / ID: 9hcl
TitleCrystal structure of human TRF1 TRFH domain in complex with compound 12
ComponentsTelomeric repeat-binding factor 1
KeywordsPROTEIN BINDING / Telomere / Shelterin / Inhibitor
Function / homology
Function and homology information


positive regulation of shelterin complex assembly / negative regulation of establishment of protein localization to telomere / negative regulation of establishment of RNA localization to telomere / negative regulation of establishment of protein-containing complex localization to telomere / negative regulation of telomere maintenance via semi-conservative replication / negative regulation of telomeric D-loop disassembly / meiotic telomere clustering / telomeric D-loop disassembly / t-circle formation / shelterin complex ...positive regulation of shelterin complex assembly / negative regulation of establishment of protein localization to telomere / negative regulation of establishment of RNA localization to telomere / negative regulation of establishment of protein-containing complex localization to telomere / negative regulation of telomere maintenance via semi-conservative replication / negative regulation of telomeric D-loop disassembly / meiotic telomere clustering / telomeric D-loop disassembly / t-circle formation / shelterin complex / Telomere C-strand synthesis initiation / double-stranded telomeric DNA binding / ankyrin repeat binding / Telomere C-strand (Lagging Strand) Synthesis / nuclear telomere cap complex / G-rich strand telomeric DNA binding / telomere capping / Processive synthesis on the C-strand of the telomere / Polymerase switching on the C-strand of the telomere / Removal of the Flap Intermediate from the C-strand / DNA binding, bending / negative regulation of telomere maintenance via telomere lengthening / telomeric DNA binding / negative regulation of DNA replication / negative regulation of telomere maintenance via telomerase / positive regulation of telomere maintenance / Telomere Extension By Telomerase / telomere maintenance via telomerase / Packaging Of Telomere Ends / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / telomere maintenance / Inhibition of DNA recombination at telomere / Meiotic synapsis / DNA Damage/Telomere Stress Induced Senescence / spindle / fibrillar center / microtubule binding / chromosome, telomeric region / nuclear body / response to xenobiotic stimulus / cell division / nucleolus / protein homodimerization activity / DNA binding / nucleoplasm / identical protein binding / nucleus / cytoplasm
Similarity search - Function
: / Telomeric repeat-binding factor 1/2 / Telomere repeat-binding factor, dimerisation domain superfamily / Telomere repeat-binding factor, dimerisation domain / Telomere repeat binding factor (TRF) / Myb-type HTH DNA-binding domain profile. / Myb domain / Myb-like DNA-binding domain / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain / Homeobox-like domain superfamily
Similarity search - Domain/homology
Chem-TWC / Telomeric repeat-binding factor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.87 Å
AuthorsCasale, G. / Le Bihan, Y.-V. / van Montfort, R.L.M. / Guettler, S.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust214311/Z/18/Z United Kingdom
CitationJournal: To Be Published
Title: Discovery of first-in-class inhibitors of the TRF1-TIN2 protein-protein interaction by fragment screening
Authors: Casale, G. / Guettler, S.
History
DepositionNov 11, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 19, 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: Telomeric repeat-binding factor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,57910
Polymers25,5561
Non-polymers1,0239
Water3,477193
1
A: Telomeric repeat-binding factor 1
hetero molecules

A: Telomeric repeat-binding factor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,15820
Polymers51,1122
Non-polymers2,04618
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_554x-y,-y,-z-1/31
Buried area5380 Å2
ΔGint-9 kcal/mol
Surface area19570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)85.918, 85.918, 91.110
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121

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Components

#1: Protein Telomeric repeat-binding factor 1 / NIMA-interacting protein 2 / TTAGGG repeat-binding factor 1 / Telomeric protein Pin2/TRF1


Mass: 25556.039 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TERF1, PIN2, TRBF1, TRF, TRF1 / Plasmid: pET His6 MBP Asn10 TEV LIC / Production host: Escherichia coli (E. coli) / Strain (production host): BL21-CodonPlus(DE3)-RIL / References: UniProt: P54274
#2: Chemical ChemComp-TWC / 2-ethyl-5-(trifluoromethyl)-2,4-dihydro-3H-pyrazol-3-one


Mass: 180.128 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: C6H7F3N2O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 193 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 3.8 Å3/Da / Density % sol: 67.62 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 150 nanoliter of TRF1 TRFH at 28.6 mg/mL plus 150 nanoliter of a crystallisation solution consisting of 0.1 M MES pH 6, 1-12 mM Mg(OAc)2, 1% PEG8000, and 10-15% glycerol, against 35 ...Details: 150 nanoliter of TRF1 TRFH at 28.6 mg/mL plus 150 nanoliter of a crystallisation solution consisting of 0.1 M MES pH 6, 1-12 mM Mg(OAc)2, 1% PEG8000, and 10-15% glycerol, against 35 microliter of crystallisation solution.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9179 Å
DetectorType: DECTRIS EIGER2 XE 9M / Detector: PIXEL / Date: Jan 20, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9179 Å / Relative weight: 1
ReflectionResolution: 1.87→74.41 Å / Num. obs: 32610 / % possible obs: 100 % / Redundancy: 9.8 % / CC1/2: 1 / Rmerge(I) obs: 0.05 / Rpim(I) all: 0.017 / Rrim(I) all: 0.052 / Χ2: 0.83 / Net I/σ(I): 19.7 / Num. measured all: 319242
Reflection shellResolution: 1.87→1.91 Å / % possible obs: 100 % / Redundancy: 8.3 % / Rmerge(I) obs: 1.791 / Num. measured all: 17040 / Num. unique obs: 2043 / CC1/2: 0.728 / Rpim(I) all: 0.658 / Rrim(I) all: 1.911 / Χ2: 0.63 / Net I/σ(I) obs: 0.8

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Processing

Software
NameVersionClassification
BUSTER2.10.4 (26-JUL-2023)refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.87→23.93 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.944 / SU R Cruickshank DPI: 0.103 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.109 / SU Rfree Blow DPI: 0.102 / SU Rfree Cruickshank DPI: 0.097
RfactorNum. reflection% reflectionSelection details
Rfree0.2203 1473 4.52 %RANDOM
Rwork0.2044 ---
obs0.2051 32553 100 %-
Displacement parametersBiso mean: 54.28 Å2
Baniso -1Baniso -2Baniso -3
1--6.4686 Å20 Å20 Å2
2---6.4686 Å20 Å2
3---12.9373 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: LAST / Resolution: 1.87→23.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1545 0 62 193 1800
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0081677HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.82260HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d609SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes288HARMONIC5
X-RAY DIFFRACTIONt_it1677HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.68
X-RAY DIFFRACTIONt_other_torsion13.93
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion222SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies7HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1631SEMIHARMONIC4
LS refinement shellResolution: 1.87→1.88 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.4346 -4.14 %
Rwork0.3387 625 -
all0.3429 652 -
obs--100 %
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)
13.0992-0.3607-2.69433.48832.09114.65050.06810.0367-0.10890.0491-0.3130.4989-0.1027-0.81920.245-0.4101-0.0195-0.0026-0.26760.0078-0.271523.7177-5.1813-15.1757
21.2086-0.33980.27064.27630.624210.59960.10160.18880.0581-0.2564-0.0436-0.0922-0.1872-0.0708-0.058-0.37630.01740.001-0.30250.0076-0.315634.0257-3.517-21.5218
36.0237-0.5844-5.4152.7815-0.38858.6926-0.02350.1033-0.1123-0.03960.13280.36170.2158-0.3453-0.1094-0.3327-0.0129-0.0282-0.2768-0.0003-0.344330.8177-14.8932-17.1366
42.7254-0.55152.32424.7094-2.216622.60450.1162-0.01070.5915-0.0292-0.2081-0.6814-1.29741.04260.0918-0.2934-0.04330.0611-0.1839-0.0248-0.310948.8051-14.4398-22.7536
56.4968-2.0246-1.95644.56771.8289.5538-0.1578-0.053-0.56820.1648-0.05340.89890.8521-1.21030.21120.01680.0129-0.0102-0.04720.0024-0.134737.5014-24.6411-27.4005
68.36827.4677-7.56629.5326-8.207911.1956-0.0198-0.6624-0.53510.1453-0.0816-0.91730.53621.34430.1014-0.1250.0376-0.0104-0.1226-0.094-0.310453.2833-23.5326-29.482
76.33721.0471-4.11123.3029-2.636310.7396-0.3565-0.1662-0.47740.02740.1292-0.02261.0263-0.03350.2274-0.2216-0.00080.0151-0.421-0.0317-0.415451.3642-30.8696-37.5857
86.5584-5.0812-7.37165.43475.76427.38140.1370.9039-0.3404-0.3999-0.64620.6404-0.1128-1.04350.5092-0.24380.0214-0.0991-0.135-0.072-0.314930.1783-19.2895-33.0714
915.8973-6.09253.073516.0912-7.806213.34840.08850.79430.8173-0.9932-0.05571.3344-0.0122-0.7844-0.0328-0.50690.0199-0.1635-0.036-0.0976-0.226613.451.1489-24.2904
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|62 - 92}
2X-RAY DIFFRACTION2{A|93 - 111}
3X-RAY DIFFRACTION3{A|112 - 134}
4X-RAY DIFFRACTION4{A|135 - 149}
5X-RAY DIFFRACTION5{A|150 - 186}
6X-RAY DIFFRACTION6{A|187 - 200}
7X-RAY DIFFRACTION7{A|201 - 225}
8X-RAY DIFFRACTION8{A|226 - 253}
9X-RAY DIFFRACTION9{A|254 - 268}

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