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- PDB-5jfs: Crystal structure of TrkA in complex with PF-00593174 -

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Basic information

Entry
Database: PDB / ID: 5jfs
TitleCrystal structure of TrkA in complex with PF-00593174
ComponentsHigh affinity nerve growth factor receptor
KeywordsHYDROLASE/HYDROLASE INHIBITOR / TrkA inhibitor complex / HYDROLASE-HYDROLASE 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 / nerve growth factor signaling pathway / axonogenesis involved in innervation / GPI-linked ephrin receptor activity / 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 synapse assembly / positive regulation of programmed cell death / 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 / neuron development / response to axon injury / 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 / cellular response to nerve growth factor stimulus / B cell differentiation / axon guidance / positive regulation of neuron projection development / receptor protein-tyrosine kinase / positive regulation of GTPase activity / kinase binding / cellular response to nicotine / circadian rhythm / peptidyl-tyrosine phosphorylation / recycling endosome membrane / neuron projection development / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of angiogenesis / 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 / positive regulation of ERK1 and ERK2 cascade / learning or memory / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / early endosome / endosome membrane / response to xenobiotic stimulus / positive regulation of protein phosphorylation / axon / negative regulation of cell population proliferation / protein phosphorylation / dendrite / neuronal cell body / 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 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / 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-6K0 / High affinity nerve growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.07 Å
AuthorsJayasankar, J. / Brown, D. / Skerratt, S. / Kurumbail, R.
CitationJournal: J. Med. Chem. / Year: 2016
Title: The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain.
Authors: Skerratt, S.E. / Andrews, M. / Bagal, S.K. / Bilsland, J. / Brown, D. / Bungay, P.J. / Cole, S. / Gibson, K.R. / Jones, R. / Morao, I. / Nedderman, A. / Omoto, K. / Robinson, C. / Ryckmans, ...Authors: Skerratt, S.E. / Andrews, M. / Bagal, S.K. / Bilsland, J. / Brown, D. / Bungay, P.J. / Cole, S. / Gibson, K.R. / Jones, R. / Morao, I. / Nedderman, A. / Omoto, K. / Robinson, C. / Ryckmans, T. / Skinner, K. / Stupple, P. / Waldron, G.
History
DepositionApr 19, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 1, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)35,5532
Polymers35,1021
Non-polymers4511
Water6,557364
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)125.220, 125.220, 46.510
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number172
Space group name H-MP64

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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 A / Trk-A / gp140trk / p140-TrkA


Mass: 35101.551 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NTRK1, MTC, TRK, TRKA / Cell line (production host): sf21s / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P04629, receptor protein-tyrosine kinase
#2: Chemical ChemComp-6K0 / N-{4-[4-amino-7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]pyridin-2-yl}-N'-(2,4-difluorophenyl)urea


Mass: 451.429 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H19F2N7O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 364 / 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 Å3/Da / Density % sol: 62.95 %
Crystal growTemperature: 277 K / Method: vapor diffusion
Details: protein was concentrated to 10mg/ml. Crystals of complexes were grown using the hanging drop vapour diffusion method from 0.1M HEPES pH7.5, 0.1M MgCl2 and 10% EtOH at 4C

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Mar 9, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.07→107.43 Å / Num. obs: 24621 / % possible obs: 98.6 % / Redundancy: 6.1 % / Biso Wilson estimate: 23.84 Å2 / Net I/σ(I): 12.3
Reflection shellResolution: 2.07→2.18 Å

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Processing

Software
NameVersionClassification
BUSTER2.9.3refinement
XDSdata reduction
SCALAdata scaling
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.07→24.3 Å / Cor.coef. Fo:Fc: 0.9617 / Cor.coef. Fo:Fc free: 0.9505 / SU R Cruickshank DPI: 0.073 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.077 / SU Rfree Blow DPI: 0.076 / SU Rfree Cruickshank DPI: 0.073
RfactorNum. reflection% reflectionSelection details
Rfree0.1909 2558 5.18 %RANDOM
Rwork0.1699 ---
obs0.171 49425 99.94 %-
Displacement parametersBiso mean: 31.97 Å2
Baniso -1Baniso -2Baniso -3
1--0.9762 Å20 Å20 Å2
2---0.9762 Å20 Å2
3---1.9524 Å2
Refine analyzeLuzzati coordinate error obs: 0.186 Å
Refinement stepCycle: 1 / Resolution: 2.07→24.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2245 0 33 364 2642
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012344HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.033179HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d798SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes60HARMONIC2
X-RAY DIFFRACTIONt_gen_planes355HARMONIC5
X-RAY DIFFRACTIONt_it2344HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.24
X-RAY DIFFRACTIONt_other_torsion17.15
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion277SEMIHARMONIC5
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_contact2859SEMIHARMONIC4
LS refinement shellResolution: 1.66→1.7 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2208 180 5.01 %
Rwork0.1947 3415 -
all0.1961 3595 -
obs--99.94 %
Refinement TLS params.Method: refined / Origin x: 14.0072 Å / Origin y: 38.0498 Å / Origin z: 2.9158 Å
111213212223313233
T-0.0647 Å2-0.0182 Å2-0.0214 Å2--0.0418 Å2-0.0037 Å2---0.0518 Å2
L0.8098 °20.4594 °2-0.7346 °2-0.9452 °2-0.2567 °2--1.2873 °2
S-0.0207 Å °0.0323 Å °0.0237 Å °-0.0503 Å °0.0666 Å °-0.011 Å °-0.0135 Å °-0.0079 Å °-0.0459 Å °
Refinement TLS groupSelection details: { A|* }

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