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- PDB-6dkw: Crystal structure of Trk-A in complex with the Pan-Trk Kinase Inh... -

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Basic information

Entry
Database: PDB / ID: 6dkw
TitleCrystal structure of Trk-A in complex with the Pan-Trk Kinase Inhibitor, compound 3.
ComponentsTyrosine-protein kinase receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Inhibitor Tyrosine kinase / TRANSFERASE / pan-Trk Kinase / Treatment for pain / 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 / 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 / nervous system development / 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 / cell differentiation / 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-GXA / Tyrosine-protein kinase receptor / High affinity nerve growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.91 Å
AuthorsGreasley, S.E. / Brown, D.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain.
Authors: Bagal, S.K. / Andrews, M. / Bechle, B.M. / Bian, J. / Bilsland, J. / Blakemore, D.C. / Braganza, J.F. / Bungay, P.J. / Corbett, M.S. / Cronin, C.N. / Cui, J.J. / Dias, R. / Flanagan, N.J. / ...Authors: Bagal, S.K. / Andrews, M. / Bechle, B.M. / Bian, J. / Bilsland, J. / Blakemore, D.C. / Braganza, J.F. / Bungay, P.J. / Corbett, M.S. / Cronin, C.N. / Cui, J.J. / Dias, R. / Flanagan, N.J. / Greasley, S.E. / Grimley, R. / James, K. / Johnson, E. / Kitching, L. / Kraus, M.L. / McAlpine, I. / Nagata, A. / Ninkovic, S. / Omoto, K. / Scales, S. / Skerratt, S.E. / Sun, J. / Tran-Dube, M. / Waldron, G.J. / Wang, F. / Warmus, J.S.
History
DepositionMay 31, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 11, 2018Provider: repository / Type: Initial release
Revision 1.1Aug 15, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Mar 13, 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: Tyrosine-protein kinase receptor
B: Tyrosine-protein kinase receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,2084
Polymers70,2032
Non-polymers1,0052
Water1,31573
1
A: Tyrosine-protein kinase receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6042
Polymers35,1021
Non-polymers5021
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6042
Polymers35,1021
Non-polymers5021
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)93.980, 93.980, 159.270
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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Components

#1: Protein Tyrosine-protein kinase receptor


Mass: 35101.551 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NTRK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: J3KP20, UniProt: P04629*PLUS, receptor protein-tyrosine kinase
#2: Chemical ChemComp-GXA / 5-(1-methyl-1H-imidazol-4-yl)-2-[(1-{[4-(trifluoromethoxy)phenyl]acetyl}piperidin-4-yl)oxy]benzamide


Mass: 502.486 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H25F3N4O4
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 73 / 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: 2.92 Å3/Da / Density % sol: 57.81 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / Details: not available

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 28, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.91→81.39 Å / Num. obs: 18303 / % possible obs: 99.3 % / Redundancy: 9.9 % / Biso Wilson estimate: 93.57 Å2 / Rsym value: 0.07 / Net I/σ(I): 18.6
Reflection shellResolution: 2.91→2.99 Å / Redundancy: 10.1 % / Mean I/σ(I) obs: 3.5 / Num. unique obs: 1321 / Rsym value: 0.609 / % possible all: 99.1

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
SCALAdata scaling
Cootmodel building
BUSTERphasing
RefinementResolution: 2.91→81.39 Å / Cor.coef. Fo:Fc: 0.888 / Cor.coef. Fo:Fc free: 0.852 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.379
RfactorNum. reflection% reflectionSelection details
Rfree0.262 931 5.1 %RANDOM
Rwork0.231 ---
obs0.233 18268 99 %-
Displacement parametersBiso mean: 95.13 Å2
Baniso -1Baniso -2Baniso -3
1--19.7419 Å20 Å20 Å2
2---19.7419 Å20 Å2
3---39.4838 Å2
Refine analyzeLuzzati coordinate error obs: 0.47 Å
Refinement stepCycle: 1 / Resolution: 2.91→81.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4433 0 72 73 4578
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014705HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.146418HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1627SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes99HARMONIC2
X-RAY DIFFRACTIONt_gen_planes753HARMONIC5
X-RAY DIFFRACTIONt_it4705HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.03
X-RAY DIFFRACTIONt_other_torsion20.98
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion553SEMIHARMONIC5
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_contact5297SEMIHARMONIC4
LS refinement shellResolution: 2.91→3.09 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.3142 145 5.13 %
Rwork0.2757 2681 -
all0.2777 2826 -
obs--97.05 %

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