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- PDB-5wr7: Crystal structure of Trk-A complexed with a selective inhibitor C... -

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Basic information

Entry
Database: PDB / ID: 5wr7
TitleCrystal structure of Trk-A complexed with a selective inhibitor CH7057288
ComponentsHigh affinity nerve growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TRK-A / KINASE DOMAIN / HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR / PROTEROS BIOSTRUCTURES GMBH / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


behavioral response to formalin induced pain / neurotrophin p75 receptor binding / olfactory nerve development / response to hydrostatic pressure / TRKA activation by NGF / PLC-gamma1 signalling / programmed cell death involved in cell development / Signalling to STAT3 / neurotrophin receptor activity / mechanoreceptor differentiation ...behavioral response to formalin induced pain / neurotrophin p75 receptor binding / olfactory nerve development / response to hydrostatic pressure / TRKA activation by NGF / PLC-gamma1 signalling / programmed cell death involved in cell development / Signalling to STAT3 / neurotrophin receptor activity / mechanoreceptor differentiation / nerve growth factor receptor activity / neurotrophin binding / Sertoli cell development / axonogenesis involved in innervation / GPI-linked ephrin receptor activity / nerve growth factor signaling pathway / Retrograde neurotrophin signalling / nerve growth factor binding / NGF-independant TRKA activation / sympathetic nervous system development / Signalling to p38 via RIT and RIN / ARMS-mediated activation / positive regulation of Ras protein signal transduction / positive regulation of programmed cell death / positive regulation of synapse assembly / PI3K/AKT activation / Frs2-mediated activation / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / detection of temperature stimulus involved in sensory perception of pain / neurotrophin TRK receptor signaling pathway / response to axon injury / neuron development / Signalling to RAS / detection of mechanical stimulus involved in sensory perception of pain / response to electrical stimulus / peptidyl-tyrosine autophosphorylation / transmembrane receptor protein tyrosine kinase activity / positive regulation of synaptic transmission, glutamatergic / response to nutrient levels / B cell differentiation / cellular response to nerve growth factor stimulus / positive regulation of GTPase activity / axon guidance / receptor protein-tyrosine kinase / kinase binding / positive regulation of neuron projection development / cellular response to nicotine / circadian rhythm / peptidyl-tyrosine phosphorylation / recycling endosome membrane / positive regulation of angiogenesis / neuron projection development / late endosome / late endosome membrane / positive regulation of NF-kappaB transcription factor activity / early endosome membrane / protein tyrosine kinase activity / neuron apoptotic process / negative regulation of neuron apoptotic process / protein autophosphorylation / learning or memory / positive regulation of ERK1 and ERK2 cascade / early endosome / receptor complex / endosome membrane / response to xenobiotic stimulus / positive regulation of protein phosphorylation / negative regulation of cell population proliferation / axon / protein phosphorylation / neuronal cell body / dendrite / negative regulation of apoptotic process / cell surface / protein homodimerization activity / protein-containing complex / ATP binding / identical protein 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-RCH / High affinity nerve growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.76 Å
AuthorsTanaka, H. / Blaesse, M. / Augustin, M. / Goesser, C.
CitationJournal: Mol. Cancer Ther. / Year: 2018
Title: Selective TRK Inhibitor CH7057288 against TRK Fusion-Driven Cancer.
Authors: Tanaka, H. / Sase, H. / Tsukaguchi, T. / Hasegawa, M. / Tanimura, H. / Yoshida, M. / Sakata, K. / Fujii, T. / Tachibana, Y. / Takanashi, K. / Higashida, A. / Hasegawa, K. / Ono, Y. / Oikawa, N. / Mio, T.
History
DepositionNov 30, 2016Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 6, 2017Provider: repository / Type: Initial release
Revision 1.1Dec 19, 2018Group: Data collection / 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: High affinity nerve growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,3162
Polymers34,7461
Non-polymers5701
Water50428
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area15330 Å2
Unit cell
Length a, b, c (Å)104.262, 104.262, 203.609
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number155
Space group name H-MH32

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Components

#1: Protein High affinity nerve growth factor receptor / Neurotrophic tyrosine kinase receptor type 1 / TRK1-transforming tyrosine kinase protein / ...Neurotrophic tyrosine kinase receptor type 1 / TRK1-transforming tyrosine kinase protein / Tropomyosin-related kinase A / Tyrosine kinase receptor / Tyrosine kinase receptor A / Trk-A / gp140trk / p140-TrkA


Mass: 34745.961 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, UNP residues 489-792
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NTRK1, MTC, TRK, TRKA / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P04629, receptor protein-tyrosine kinase
#2: Chemical ChemComp-RCH / N-tert-butyl-2-[2-[6,6-dimethyl-8-(methylsulfonylamino)-11-oxidanylidene-naphtho[2,3-b][1]benzofuran-3-yl]ethynyl]-6-methyl-pyridine-4-carboxamide


Mass: 569.671 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H31N3O5S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 28 / Source method: isolated from a natural source / Formula: H2O

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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: 3.11 Å3/Da / Density % sol: 60.52 %
Crystal growTemperature: 277 K / Method: vapor diffusion
Details: 0.05-0.15M KH2PO4, 0.1M MES pH 6.25, 1.5-2.5M NaCl, 0.05-0.15M NaH2PO4, 0.01M TCEP HCl

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.97949 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Jan 15, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 2.76→82.54 Å / Num. obs: 11208 / % possible obs: 99.7 % / Observed criterion σ(I): 0 / Redundancy: 4.9 % / Rmerge(I) obs: 0.119 / Net I/σ(I): 13.7
Reflection shellResolution: 2.76→3.01 Å / Redundancy: 5 % / Rmerge(I) obs: 0.435 / Mean I/σ(I) obs: 4.6 / Num. unique all: 2525 / % possible all: 100

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.8.0049refinement
REFMAC5.8.0049phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: RIGID BODY

Resolution: 2.76→82.54 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.893 / SU B: 24.176 / SU ML: 0.239 / Cross valid method: THROUGHOUT / ESU R: 0.946 / ESU R Free: 0.316 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23434 721 6.4 %RANDOM
Rwork0.20634 ---
obs0.20818 10486 99.66 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 40.719 Å2
Baniso -1Baniso -2Baniso -3
1-0.51 Å20.25 Å20 Å2
2--0.51 Å20 Å2
3----1.65 Å2
Refinement stepCycle: LAST / Resolution: 2.76→82.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2426 0 41 28 2495
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0192430
X-RAY DIFFRACTIONr_bond_other_d0.0010.022288
X-RAY DIFFRACTIONr_angle_refined_deg1.1971.9773314
X-RAY DIFFRACTIONr_angle_other_deg2.58235202
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9665300
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.48322.871101
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.63415369
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.791516
X-RAY DIFFRACTIONr_chiral_restr0.0630.2355
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212762
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02578
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_it1.8082.691206
X-RAY DIFFRACTIONr_mcbond_other1.8082.6891205
X-RAY DIFFRACTIONr_mcangle_it3.1584.5321504
X-RAY DIFFRACTIONr_mcangle_other3.1574.5341505
X-RAY DIFFRACTIONr_scbond_it2.0032.8231224
X-RAY DIFFRACTIONr_scbond_other2.0022.8231225
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.2974.6571811
X-RAY DIFFRACTIONr_long_range_B_refined4.93711.6932658
X-RAY DIFFRACTIONr_long_range_B_other4.93711.6952659
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.76→2.832 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.44 47 -
Rwork0.299 765 -
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)
11.5377-0.64911.18254.1309-0.27556.5154-0.17790.11230.36350.02590.08940.0562-0.6199-0.21420.08860.15880.039-0.05650.17330.00110.1382-13.613-15.60214.999
23.48490.1909-0.4551.7695-0.73422.955-0.0204-0.077-0.04290.05140.0625-0.08920.01090.1296-0.0420.09450.0165-0.00230.06630.00080.00861.909-35.95913.547
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A489 - 592
2X-RAY DIFFRACTION2A593 - 792

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