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- PDB-5kmm: TrkA JM-kinase with 1-(2-methyl-4-phenyl-pyrimidin-5-yl)-3-(1-nap... -

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Basic information

Entry
Database: PDB / ID: 5kmm
TitleTrkA JM-kinase with 1-(2-methyl-4-phenyl-pyrimidin-5-yl)-3-(1-naphthyl)urea
ComponentsHigh affinity nerve growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / juxtamembrane / inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


neurotrophin p75 receptor binding / behavioral response to formalin induced pain / olfactory nerve development / TRKA activation by NGF / PLC-gamma1 signalling / Signalling to STAT3 / programmed cell death involved in cell development / response to hydrostatic pressure / neurotrophin receptor activity / mechanoreceptor differentiation ...neurotrophin p75 receptor binding / behavioral response to formalin induced pain / olfactory nerve development / TRKA activation by NGF / PLC-gamma1 signalling / Signalling to STAT3 / programmed cell death involved in cell development / response to hydrostatic pressure / neurotrophin receptor activity / mechanoreceptor differentiation / nerve growth factor receptor activity / neurotrophin binding / GPI-linked ephrin receptor activity / nerve growth factor signaling pathway / axonogenesis involved in innervation / nerve growth factor binding / Sertoli cell development / Retrograde neurotrophin signalling / sympathetic nervous system development / NGF-independant TRKA activation / Signalling to p38 via RIT and RIN / ARMS-mediated activation / positive regulation of programmed cell death / positive regulation of Ras protein signal transduction / positive regulation of synapse assembly / PI3K/AKT activation / peptidyl-tyrosine autophosphorylation / Frs2-mediated activation / neurotrophin TRK receptor signaling pathway / detection of temperature stimulus involved in sensory perception of pain / positive regulation of GTPase activity / response to electrical stimulus / Signalling to RAS / detection of mechanical stimulus involved in sensory perception of pain / neuron development / positive regulation of synaptic transmission, glutamatergic / response to axon injury / transmembrane receptor protein tyrosine kinase activity / axon guidance / cell surface receptor protein tyrosine kinase signaling pathway / peptidyl-tyrosine phosphorylation / B cell differentiation / response to nutrient levels / positive regulation of NF-kappaB transcription factor activity / positive regulation of neuron projection development / circadian rhythm / receptor protein-tyrosine kinase / cellular response to nerve growth factor stimulus / cellular response to nicotine / kinase binding / recycling endosome membrane / positive regulation of angiogenesis / neuron projection development / late endosome membrane / late endosome / protein autophosphorylation / protein tyrosine kinase activity / neuron apoptotic process / early endosome membrane / spermatogenesis / negative regulation of neuron apoptotic process / learning or memory / early endosome / positive regulation of ERK1 and ERK2 cascade / protein phosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / endosome membrane / response to xenobiotic stimulus / negative regulation of cell population proliferation / axon / neuronal cell body / dendrite / negative regulation of apoptotic process / cell surface / protein homodimerization activity / protein-containing complex / mitochondrion / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-6UJ / High affinity nerve growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.12 Å
AuthorsSu, H.P.
CitationJournal: Proc. Natl. Acad. Sci. U.S.A. / Year: 2017
Title: Structural characterization of nonactive site, TrkA-selective kinase inhibitors.
Authors: Su, H.P. / Rickert, K. / Burlein, C. / Narayan, K. / Bukhtiyarova, M. / Hurzy, D.M. / Stump, C.A. / Zhang, X. / Reid, J. / Krasowska-Zoladek, A. / Tummala, S. / Shipman, J.M. / Kornienko, M. ...Authors: Su, H.P. / Rickert, K. / Burlein, C. / Narayan, K. / Bukhtiyarova, M. / Hurzy, D.M. / Stump, C.A. / Zhang, X. / Reid, J. / Krasowska-Zoladek, A. / Tummala, S. / Shipman, J.M. / Kornienko, M. / Lemaire, P.A. / Krosky, D. / Heller, A. / Achab, A. / Chamberlin, C. / Saradjian, P. / Sauvagnat, B. / Yang, X. / Ziebell, M.R. / Nickbarg, E. / Sanders, J.M. / Bilodeau, M.T. / Carroll, S.S. / Lumb, K.J. / Soisson, S.M. / Henze, D.A. / Cooke, A.J.
History
DepositionJun 27, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 28, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 18, 2017Group: Database references
Revision 1.2Feb 1, 2017Group: Database references
Revision 1.3Sep 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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)37,6212
Polymers37,2671
Non-polymers3541
Water77543
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.060, 52.060, 226.030
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number151
Space group name H-MP3112

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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: 37266.746 Da / Num. of mol.: 1
Fragment: catalytic domain with juxtamembrane region, UNP residues 376-698
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-6UJ / 1-(2-methyl-4-phenyl-pyrimidin-5-yl)-3-naphthalen-1-yl-urea


Mass: 354.405 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H18N4O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 43 / 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: 2.37 Å3/Da / Density % sol: 48.16 % / Mosaicity: 0 °
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 50mM MES pH 6.5, 150 mM NaCl, 5mM TCEP, 0.1% beta-OctylGlucoside

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 16, 2012
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.117→44.22 Å / Num. all: 20606 / Num. obs: 20606 / % possible obs: 100 % / Redundancy: 9.6 % / Biso Wilson estimate: 46.37 Å2 / Rpim(I) all: 0.015 / Rrim(I) all: 0.048 / Rsym value: 0.043 / Net I/av σ(I): 13.091 / Net I/σ(I): 30.2 / Num. measured all: 197090
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
2.12-2.238.30.5131.52453229570.2020.5840.5134.1100
2.23-2.379.40.3452.22698228630.1250.3840.3456.6100
2.37-2.5310.20.2033.72621125780.070.2240.20311.1100
2.53-2.7310.10.1295.82539225020.0440.1420.12916.7100
2.73-2.999.70.0769.72200822690.0270.0850.07626.2100
2.99-3.3510.20.04815.22112020700.0170.0540.04841.1100
3.35-3.879.60.03320.91761618290.0120.0370.03357.7100
3.87-4.739.80.02526.21562015870.0090.0280.02575100
4.73-6.699.20.02526.31128812280.0090.0280.02574.2100
6.69-45.2068.70.02125.863217230.0080.0240.02183.699.7

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Processing

Software
NameVersionClassification
SCALA3.3.16data scaling
BUSTER-TNTrefinement
PDB_EXTRACT3.2data extraction
XDSdata reduction
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4pmm

4pmm


Resolution: 2.12→44.22 Å / Cor.coef. Fo:Fc: 0.9414 / Cor.coef. Fo:Fc free: 0.9242 / SU R Cruickshank DPI: 0.215 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.212 / SU Rfree Blow DPI: 0.189 / SU Rfree Cruickshank DPI: 0.192
RfactorNum. reflection% reflectionSelection details
Rfree0.2642 1049 5.13 %RANDOM
Rwork0.2136 ---
obs0.2161 20453 99.98 %-
Displacement parametersBiso max: 131.08 Å2 / Biso mean: 51.87 Å2 / Biso min: 19.22 Å2
Baniso -1Baniso -2Baniso -3
1--0.9141 Å20 Å20 Å2
2---0.9141 Å20 Å2
3---1.8282 Å2
Refine analyzeLuzzati coordinate error obs: 0.329 Å
Refinement stepCycle: final / Resolution: 2.12→44.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2361 0 27 43 2431
Biso mean--44.84 39.5 -
Num. residues----301
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d829SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes48HARMONIC8
X-RAY DIFFRACTIONt_gen_planes392HARMONIC8
X-RAY DIFFRACTIONt_it2449HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion297SEMIHARMONIC5
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_contact2794SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2449HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3316HARMONIC21.07
X-RAY DIFFRACTIONt_omega_torsion2.1
X-RAY DIFFRACTIONt_other_torsion18.99
LS refinement shellResolution: 2.12→2.23 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.3008 151 5.13 %
Rwork0.2569 2792 -
all0.2591 2943 -
obs--99.98 %

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