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- PDB-5h3q: Crystal Structure of TrkA kinase with ligand -

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Basic information

Entry
Database: PDB / ID: 5h3q
TitleCrystal Structure of TrkA kinase with ligand
ComponentsHigh affinity nerve growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TrkA inhibitor / 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 / axon guidance / receptor protein-tyrosine kinase / positive regulation of GTPase activity / 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 / early endosome / learning or memory / positive regulation of ERK1 and ERK2 cascade / 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-7HF / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / High affinity nerve growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsNoritaka, F.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: The juxtamembrane region of TrkA kinase is critical for inhibitor selectivity
Authors: Furuya, N. / Momose, T. / Katsuno, K. / Fushimi, N. / Muranaka, H. / Handa, C. / Ozawa, T. / Kinoshita, T.
History
DepositionOct 26, 2016Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 22, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 8, 2017Group: Database references
Revision 1.2Feb 26, 2020Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.3Nov 8, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)37,3265
Polymers36,4951
Non-polymers8314
Water1,69394
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area140 Å2
ΔGint-12 kcal/mol
Surface area14550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)140.845, 157.195, 52.306
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number21
Space group name H-MC222

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Components

#1: Protein High affinity nerve growth factor receptor / TrkA kinase / Neurotrophic tyrosine kinase receptor type 1 / TRK1-transforming tyrosine kinase ...TrkA kinase / 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: 36494.926 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NTRK1, MTC, TRK, TRKA / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P04629, receptor protein-tyrosine kinase
#2: Chemical ChemComp-7HF / 1-[(3S,4R)-4-[3,4-bis(fluoranyl)phenyl]-1-(2-methoxyethyl)pyrrolidin-3-yl]-3-(5-ethoxy-4-methyl-2-phenyl-pyrazol-3-yl)urea


Mass: 499.553 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H31F2N5O3
#3: Chemical ChemComp-DTT / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / 1,4-DITHIOTHREITOL / Dithiothreitol


Mass: 154.251 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O2S2
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 94 / 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: 3.97 Å3/Da / Density % sol: 68.99 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 1.2M Sodium Tartrate, 100mM Tris-HCl pH 8.5, 5 mM DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 15, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→49.1 Å / Num. obs: 32612 / % possible obs: 99.67 % / Redundancy: 6.6 % / Rmerge(I) obs: 0.114 / Net I/σ(I): 13.98
Reflection shellResolution: 2.1→2.16 Å / Rmerge(I) obs: 1.688 / Rejects: 0

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
XDSdata reduction
XDSdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4F0I

4f0i


Resolution: 2.1→46.81 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.953 / WRfactor Rfree: 0.1909 / WRfactor Rwork: 0.1665 / FOM work R set: 0.7829 / SU B: 4.599 / SU ML: 0.112 / SU R Cruickshank DPI: 0.137 / SU Rfree: 0.1295 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.137 / ESU R Free: 0.129 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2151 1704 5 %RANDOM
Rwork0.1884 ---
obs0.1898 32367 99.48 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 120.09 Å2 / Biso mean: 45.184 Å2 / Biso min: 23.4 Å2
Baniso -1Baniso -2Baniso -3
1-2.93 Å20 Å2-0 Å2
2---0.98 Å20 Å2
3----1.95 Å2
Refinement stepCycle: final / Resolution: 2.1→46.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2387 0 53 94 2534
Biso mean--49.85 47.57 -
Num. residues----303
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.0192518
X-RAY DIFFRACTIONr_bond_other_d0.0040.022382
X-RAY DIFFRACTIONr_angle_refined_deg2.1371.9683412
X-RAY DIFFRACTIONr_angle_other_deg1.2873.0065449
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6285303
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.23322.931116
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.44115403
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.0331520
X-RAY DIFFRACTIONr_chiral_restr0.1330.2364
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.0212838
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02615
X-RAY DIFFRACTIONr_mcbond_it3.9434.1471216
X-RAY DIFFRACTIONr_mcbond_other3.9424.1491217
X-RAY DIFFRACTIONr_mcangle_it5.5616.1911519
LS refinement shellResolution: 2.104→2.159 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.424 120 -
Rwork0.385 2285 -
all-2405 -
obs--97.13 %

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