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- PDB-5kmn: TrkA JM-kinase with 1-(2-methyl-4-phenyl-pyrimidin-5-yl)-3-[[2-(t... -

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Basic information

Entry
Database: PDB / ID: 5kmn
TitleTrkA JM-kinase with 1-(2-methyl-4-phenyl-pyrimidin-5-yl)-3-[[2-(trifluoromethyl)phenyl]methyl]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 / circadian rhythm / positive regulation of neuron projection development / 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 / neuron apoptotic process / protein tyrosine kinase activity / 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 / axon / negative regulation of cell population proliferation / 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-6UK / High affinity nerve growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.14 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 1.3Oct 23, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
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)37,6792
Polymers37,2931
Non-polymers3861
Water1,58588
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area200 Å2
ΔGint-2 kcal/mol
Surface area14360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.150, 52.150, 228.530
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: 37292.785 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-6UK / 1-(2-methyl-4-phenyl-pyrimidin-5-yl)-3-[[2-(trifluoromethyl)phenyl]methyl]urea


Mass: 386.370 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H17F3N4O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 88 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.41 Å3/Da / Density % sol: 48.93 % / 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: Oct 26, 2012
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.136→44.3 Å / Num. all: 20356 / Num. obs: 20356 / % possible obs: 100 % / Redundancy: 9.9 % / Biso Wilson estimate: 36.13 Å2 / Rpim(I) all: 0.049 / Rrim(I) all: 0.155 / Rsym value: 0.14 / Net I/av σ(I): 3.091 / Net I/σ(I): 11.9 / Num. measured all: 201423
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
2.14-2.25100.5151.42957729430.1790.5690.5154.3100
2.25-2.399.80.37522706527720.1330.4170.3755.6100
2.39-2.5510.10.2652.72623425850.0920.2940.2658100
2.55-2.7610.20.2033.42520024620.070.2250.20310.1100
2.76-3.029.70.15742172522340.0560.1750.15712.9100
3.02-3.38100.1344.42045220470.0470.1480.13416.3100
3.38-3.9100.1214.71816118150.0420.1330.12119100
3.9-4.789.40.1094.91477315670.0390.1220.10920.9100
4.78-6.759.80.1114.91184912110.0390.1220.11120.7100
6.75-44.3048.90.1034.463877200.0390.1150.10320.699.7

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Processing

Software
NameVersionClassification
SCALA3.3.16data scaling
BUSTER-TNTrefinement
PDB_EXTRACT3.2data extraction
XDSdata reduction
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.14→44.3 Å / Cor.coef. Fo:Fc: 0.9394 / Cor.coef. Fo:Fc free: 0.92 / SU R Cruickshank DPI: 0.2 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.202 / SU Rfree Blow DPI: 0.164 / SU Rfree Cruickshank DPI: 0.165
RfactorNum. reflection% reflectionSelection details
Rfree0.2223 1030 5.1 %RANDOM
Rwork0.1936 ---
obs0.1951 20182 100 %-
Displacement parametersBiso max: 123.36 Å2 / Biso mean: 37.66 Å2 / Biso min: 12.81 Å2
Baniso -1Baniso -2Baniso -3
1--1.5858 Å20 Å20 Å2
2---1.5858 Å20 Å2
3---3.1716 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: final / Resolution: 2.14→44.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2333 0 28 88 2449
Biso mean--25.09 35.41 -
Num. residues----297
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d820SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes49HARMONIC8
X-RAY DIFFRACTIONt_gen_planes376HARMONIC8
X-RAY DIFFRACTIONt_it2419HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion295SEMIHARMONIC5
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_contact2768SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2419HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3277HARMONIC21.01
X-RAY DIFFRACTIONt_omega_torsion2.21
X-RAY DIFFRACTIONt_other_torsion16.19
LS refinement shellResolution: 2.14→2.26 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2546 148 5.04 %
Rwork0.2104 2786 -
all0.2125 2934 -
obs--100 %

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