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- PDB-7vko: Crystal structure of TrkA kinase with repotrectinib -

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Basic information

Entry
Database: PDB / ID: 7vko
TitleCrystal structure of TrkA kinase with repotrectinib
ComponentsTyrosine-protein kinase receptor
KeywordsTRANSFERASE / TRK / NTRK / macrocyclic inhibitor / drug resistance / repotrectinib
Function / homology
Function and homology information


neurotrophin receptor activity / cell surface receptor protein tyrosine kinase signaling pathway / transmembrane receptor protein tyrosine kinase activity / receptor protein-tyrosine kinase / nervous system development / cell differentiation / ATP binding / plasma membrane
Similarity search - Function
High affinity nerve growth factor receptor NTRK1 / Tyrosine kinase receptor A, transmembrane domain / Tyrosine kinase receptor A trans-membrane domain / Growth factor receptor NTRK / Growth factor receptor NTRK, leucine rich repeat C-terminal / Leucine rich repeat C-terminal motif / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. ...High affinity nerve growth factor receptor NTRK1 / Tyrosine kinase receptor A, transmembrane domain / Tyrosine kinase receptor A trans-membrane domain / Growth factor receptor NTRK / Growth factor receptor NTRK, leucine rich repeat C-terminal / Leucine rich repeat C-terminal motif / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Leucine rich repeat / : / Leucine-rich repeat / Leucine-rich repeat domain superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Repotrectinib / Tyrosine-protein kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsMurray, B.W. / Rogers, E. / Zhai, D. / Deng, W. / Chen, X. / Sprengeler, P.A. / Zhang, X. / Graber, A. / Reich, S.H. / Stopatschinskaja, S. ...Murray, B.W. / Rogers, E. / Zhai, D. / Deng, W. / Chen, X. / Sprengeler, P.A. / Zhang, X. / Graber, A. / Reich, S.H. / Stopatschinskaja, S. / Solomon, B. / Besse, B. / Drilon, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Mol.Cancer Ther. / Year: 2021
Title: Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations.
Authors: Murray, B.W. / Rogers, E. / Zhai, D. / Deng, W. / Chen, X. / Sprengeler, P.A. / Zhang, X. / Graber, A. / Reich, S.H. / Stopatschinskaja, S. / Solomon, B. / Besse, B. / Drilon, A.
History
DepositionSep 30, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 13, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Nov 29, 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: Tyrosine-protein kinase receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0717
Polymers37,2361
Non-polymers8366
Water37821
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area200 Å2
ΔGint-15 kcal/mol
Surface area14870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)104.761, 104.761, 204.506
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number155
Space group name H-MH32
Components on special symmetry positions
IDModelComponents
11A-915-

HOH

21A-921-

HOH

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Components

#1: Protein Tyrosine-protein kinase receptor


Mass: 37235.777 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NTRK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: J3KP20, receptor protein-tyrosine kinase
#2: Chemical ChemComp-7GI / Repotrectinib / TPX-0005


Mass: 355.366 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18FN5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 21 / Source method: isolated from a natural source / Formula: H2O
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: 2.9 Å3/Da / Density % sol: 57.59 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.1M citric acid PH 5.0, 8M ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.97934 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Sep 10, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97934 Å / Relative weight: 1
ReflectionResolution: 2.9→44.54 Å / Num. obs: 9735 / % possible obs: 99 % / Redundancy: 2.8 % / Rmerge(I) obs: 0.059 / Net I/σ(I): 8.2
Reflection shellResolution: 2.9→3.08 Å / Rmerge(I) obs: 0.49 / Num. unique obs: 1555

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4yne

4yne


Resolution: 2.9→44.58 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.915 / SU B: 19.961 / SU ML: 0.343 / Cross valid method: THROUGHOUT / ESU R Free: 0.407 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26738 491 5 %RANDOM
Rwork0.18412 ---
obs0.18843 9242 98.61 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 95.454 Å2
Baniso -1Baniso -2Baniso -3
1-2.74 Å21.37 Å20 Å2
2--2.74 Å20 Å2
3----8.89 Å2
Refinement stepCycle: 1 / Resolution: 2.9→44.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2363 0 51 21 2435
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0132471
X-RAY DIFFRACTIONr_bond_other_d0.0020.0172275
X-RAY DIFFRACTIONr_angle_refined_deg1.7041.6553352
X-RAY DIFFRACTIONr_angle_other_deg1.2591.5855241
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.8735296
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.90420.357140
X-RAY DIFFRACTIONr_dihedral_angle_3_deg23.84515405
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.1651524
X-RAY DIFFRACTIONr_chiral_restr0.0660.2296
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022761
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02567
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it9.1349.8591189
X-RAY DIFFRACTIONr_mcbond_other9.1319.8571190
X-RAY DIFFRACTIONr_mcangle_it13.45214.7811483
X-RAY DIFFRACTIONr_mcangle_other13.44714.7791484
X-RAY DIFFRACTIONr_scbond_it9.40910.5981279
X-RAY DIFFRACTIONr_scbond_other9.03910.4831260
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other13.62515.4031839
X-RAY DIFFRACTIONr_long_range_B_refined18.1242800
X-RAY DIFFRACTIONr_long_range_B_other18.122801
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.9→2.976 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.44 37 -
Rwork0.377 674 -
obs--99.58 %

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