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- PDB-8j5x: The crystal structure of TrkA(G595R) kinase in complex with N-(3-... -

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Basic information

Entry
Database: PDB / ID: 8j5x
TitleThe crystal structure of TrkA(G595R) kinase in complex with N-(3-cyclopropyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-4^6-methyl-14-oxo-5-oxa-13-aza-1(3,6)-imidazo[1,2-b]pyridazina-4(1,3)-benzenacyclotetradecaphan-2-yne-4^5-carboxamide
ComponentsHigh affinity nerve growth factor receptor
KeywordsTRANSFERASE
Function / homology
Function and homology information


neurotrophin p75 receptor binding / behavioral response to formalin induced pain / olfactory nerve development / response to hydrostatic pressure / TRKA activation by NGF / PLC-gamma1 signalling / Signalling to STAT3 / neurotrophin receptor activity / programmed cell death involved in cell development / mechanoreceptor differentiation ...neurotrophin p75 receptor binding / behavioral response to formalin induced pain / olfactory nerve development / response to hydrostatic pressure / TRKA activation by NGF / PLC-gamma1 signalling / Signalling to STAT3 / neurotrophin receptor activity / programmed cell death involved in cell development / mechanoreceptor differentiation / nerve growth factor receptor activity / neurotrophin binding / nerve growth factor signaling pathway / axonogenesis involved in innervation / Sertoli cell development / Retrograde neurotrophin signalling / nerve growth factor binding / sympathetic nervous system development / NGF-independant TRKA activation / 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 / neurotrophin TRK receptor signaling pathway / detection of temperature stimulus involved in sensory perception of pain / Signalling to RAS / response to axon injury / neuron development / 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 GTPase activity / B cell differentiation / positive regulation of synaptic transmission, glutamatergic / axon guidance / cell surface receptor protein tyrosine kinase signaling pathway / cellular response to nerve growth factor stimulus / response to nutrient levels / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / positive regulation of neuron projection development / cellular response to nicotine / kinase binding / recycling endosome membrane / circadian rhythm / positive regulation of angiogenesis / neuron projection development / positive regulation of NF-kappaB transcription factor activity / late endosome membrane / late endosome / protein autophosphorylation / protein tyrosine kinase activity / early endosome membrane / neuron apoptotic process / spermatogenesis / negative regulation of neuron apoptotic process / learning or memory / early endosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of ERK1 and ERK2 cascade / endosome membrane / protein phosphorylation / 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 / 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
Similarity search - Domain/homology
Chem-A4U / High affinity nerve growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.09192247704 Å
AuthorsZhang, Z.M. / Wang, Y.J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Structure-Based Optimization of the Third Generation Type II Macrocycle TRK Inhibitors with Improved Activity against Solvent-Front, xDFG, and Gatekeeper Mutations.
Authors: Wang, Z. / Wang, J. / Wang, Y. / Xiang, S. / Zhou, H. / Song, S. / Song, X. / Tu, Z. / Zhou, Y. / Ding, K. / Zhang, Z.M. / Zhang, Z. / Lu, X.
History
DepositionApr 24, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Sep 20, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)34,6672
Polymers34,0071
Non-polymers6601
Water3,603200
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)51.843, 51.843, 229.331
Angle α, β, γ (deg.)90.0, 90.0, 120.0
Int Tables number151
Space group name H-MP3112
Space group name HallP312(x,y,z+1/3)
Symmetry operation#1: x,y,z
#2: -y,x-y,z+1/3
#3: -x+y,-x,z+2/3
#4: -y,-x,-z+2/3
#5: -x+y,y,-z+1/3
#6: x,x-y,-z

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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: 34007.281 Da / Num. of mol.: 1 / Mutation: G595R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NTRK1, MTC, TRK, TRKA / Production host: Baculovirus expression vector pFastBac1-HM
References: UniProt: P04629, receptor protein-tyrosine kinase
#2: Chemical ChemComp-A4U / N-(3-cyclopropyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-4^6-methyl-14-oxo-5-oxa-13-aza-1(3,6)-imidazo[1,2-b]pyridazina-4(1,3)-benzenacyclotetradecaphan-2-yne-4^5-carboxamide


Mass: 659.820 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C39H45N7O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 200 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.62 Å3/Da / Density % sol: 52.98 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / Details: 0.1M Na2HPO4/KH2PO4 (pH 6.2), 2M NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CAMD / Beamline: GCPCC / Wavelength: 0.978 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Dec 9, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.978 Å / Relative weight: 1
ReflectionResolution: 2.09→39 Å / Num. obs: 21314 / % possible obs: 99.6 % / Redundancy: 8.3 % / Biso Wilson estimate: 37.81 Å2 / CC1/2: 0.977 / Net I/σ(I): 8.15
Reflection shellResolution: 2.09→2.16 Å / Num. unique obs: 21314 / CC1/2: 0.702

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Processing

Software
NameVersionClassification
PHENIX1.9_1692+SVNrefinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.09192247704→38.713941228 Å / SU ML: 0.208522184851 / Cross valid method: FREE R-VALUE / σ(F): 1.34361798361 / Phase error: 21.29911412
RfactorNum. reflection% reflection
Rfree0.220112735617 2031 9.52894810922 %
Rwork0.180103673153 19283 -
obs0.183981532313 21314 99.6167507945 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 37.7677335303 Å2
Refinement stepCycle: LAST / Resolution: 2.09192247704→38.713941228 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2340 0 49 200 2589
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.006917351747572454
X-RAY DIFFRACTIONf_angle_d1.123774730913329
X-RAY DIFFRACTIONf_chiral_restr0.0409100829964355
X-RAY DIFFRACTIONf_plane_restr0.00507943510615424
X-RAY DIFFRACTIONf_dihedral_angle_d16.4030862781896
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.14060.2574773995981300.2256257243441224X-RAY DIFFRACTION95.4866008463
2.1406-2.19410.2651830826151350.206808802661261X-RAY DIFFRACTION99.8569384835
2.1941-2.25340.2707818758261340.2040588651621292X-RAY DIFFRACTION99.7202797203
2.2534-2.31970.2316456063081300.2017392321981238X-RAY DIFFRACTION100
2.3197-2.39460.2470787935921340.2014780522781270X-RAY DIFFRACTION99.8577524893
2.3946-2.48020.2257837048811330.1907819535981297X-RAY DIFFRACTION100
2.4802-2.57940.2322577932761310.1966175831721295X-RAY DIFFRACTION100
2.5794-2.69680.2800775688271340.2009009896851264X-RAY DIFFRACTION100
2.6968-2.8390.2264295615411340.1959677775691279X-RAY DIFFRACTION99.9292786421
2.839-3.01680.2738461872451380.2004904931921284X-RAY DIFFRACTION100
3.0168-3.24960.2222882039911420.1938244812861309X-RAY DIFFRACTION100
3.2496-3.57640.1985893128831320.1683962918851271X-RAY DIFFRACTION99.9287749288
3.5764-4.09340.1665665403771350.1482633453481309X-RAY DIFFRACTION100
4.0934-5.15530.2045692125321400.1489696578051332X-RAY DIFFRACTION100
5.1553-100.2054376827831490.1823828178851358X-RAY DIFFRACTION99.7352746525
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.8035498479320.00666332123965-0.1909998589443.339175932490.09467410057561.7532963218-0.0694007091344-0.0630150780007-0.1311916580420.1433011646120.01706071786150.2054170455050.157624025905-0.02501281982320.01667663124450.175448058858-0.0059602936781-0.01602429065050.192907103159-0.0003635811912840.216807374899-15.578233903716.862811824244.778523449
22.13377575620.904451467305-0.8555322187982.41093597182.075913718563.653723252440.00373144918821-0.276759901229-0.127638611230.4031248508840.113666661345-0.2037461072750.4887460700640.268689075575-0.1093121990480.3502159280220.0416726173566-0.07418632409990.215756570868-0.001760807658860.193476152457-3.2216420288928.0063212219257.613637217
31.90052642225-0.1503761797041.178111927381.31417671828-0.5328633500971.42382003609-0.166258027524-0.1757728479510.2255658347960.1809048053220.03028813720870.190259804217-0.382223697731-0.1870709730640.1312898119690.3508222972120.0621742346358-0.01464682307690.170178491389-0.05468709111180.257477947114-14.179962081640.8367971036252.08825032
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 500 through 666 )
2X-RAY DIFFRACTION2chain 'A' and (resid 667 through 705 )
3X-RAY DIFFRACTION3chain 'A' and (resid 706 through 795 )

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