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- PDB-8j5w: The crystal structure of TrkA(F589L) kinase in complex with N-(3-... -

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Basic information

Entry
Database: PDB / ID: 8j5w
TitleThe crystal structure of TrkA(F589L) 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 / programmed cell death involved in cell development / neurotrophin receptor activity / 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 / programmed cell death involved in cell development / neurotrophin receptor activity / mechanoreceptor differentiation / nerve growth factor receptor activity / neurotrophin binding / GPI-linked ephrin receptor activity / axonogenesis involved in innervation / nerve growth factor signaling pathway / 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 / positive regulation of synaptic transmission, glutamatergic / neuron development / 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 / receptor protein-tyrosine kinase / circadian rhythm / positive regulation of neuron projection development / 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 / endosome membrane / positive regulation of ERK1 and ERK2 cascade / protein phosphorylation / receptor complex / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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: 2.28041464539 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)36,1192
Polymers35,4591
Non-polymers6601
Water00
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)51.677, 51.677, 229.152
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: 35458.855 Da / Num. of mol.: 1 / Mutation: F589L
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
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: 2.61 Å3/Da / Density % sol: 52.83 %
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: 0.97869 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Dec 26, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97869 Å / Relative weight: 1
ReflectionResolution: 2.28→30 Å / Num. obs: 16465 / % possible obs: 100 % / Redundancy: 19.3 % / Biso Wilson estimate: 40.3248038547 Å2 / CC1/2: 0.972 / Net I/σ(I): 7.5
Reflection shellResolution: 2.28→2.36 Å / Num. unique obs: 16465 / CC1/2: 0.516

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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: 2.28041464539→29.0514180951 Å / SU ML: 0.387935549589 / Cross valid method: FREE R-VALUE / σ(F): 1.51788872695 / Phase error: 28.7236336692
RfactorNum. reflection% reflection
Rfree0.265992005805 1650 10.0212572123 %
Rwork0.216913692069 14815 -
obs0.221738725573 16465 99.9635723393 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 56.0588333871 Å2
Refinement stepCycle: LAST / Resolution: 2.28041464539→29.0514180951 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2368 0 49 0 2417
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002960653344792479
X-RAY DIFFRACTIONf_angle_d0.7656184010693356
X-RAY DIFFRACTIONf_chiral_restr0.027614275039356
X-RAY DIFFRACTIONf_plane_restr0.00261821186344428
X-RAY DIFFRACTIONf_dihedral_angle_d15.4542969383910
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2805-2.34750.3818995104721380.3473066141291246X-RAY DIFFRACTION99.9277978339
2.3475-2.42320.3522479692011350.3183890682021184X-RAY DIFFRACTION100
2.4232-2.50980.3272288394071360.3018287188521197X-RAY DIFFRACTION100
2.5098-2.61020.3483534667911380.2859662243741240X-RAY DIFFRACTION99.9274836838
2.6102-2.72890.3756761799491340.267680820691243X-RAY DIFFRACTION100
2.7289-2.87270.2770743041921390.2502255704811218X-RAY DIFFRACTION99.9263622975
2.8727-3.05250.2762682924141340.234645525941217X-RAY DIFFRACTION100
3.0525-3.28790.2918275763351370.2338511737411216X-RAY DIFFRACTION100
3.2879-3.61820.2558664993721380.2077511305651231X-RAY DIFFRACTION100
3.6182-4.14050.2250536117981400.1729720210271238X-RAY DIFFRACTION100
4.1405-5.21160.2234514043471400.1722487723821281X-RAY DIFFRACTION100
5.2116-100.2306808953131410.1917915271731304X-RAY DIFFRACTION99.7928176796
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)
11.96743322079-0.0954781441157-0.4095196867334.72169370941-1.393488811833.19593173733-0.042808432247-0.08751894548710.1266652682960.11474150292-0.145483859182-0.31426861195-0.3135657716270.05433094103330.1393255361070.275170587804-0.0117506498008-0.001318838626140.225443006316-0.03447349855040.247991299966-10.0966142581-1.5297404293616.229934011
24.24665761191.29706436656-2.171056888630.8379528599190.1284417433073.70069114742-0.237664212052-0.293467343179-0.2032640483980.03462570760220.0158688034474-0.2201135208780.3380332036850.03659762041630.1624162544020.5576015249720.0772059394760.04345582166960.1984570202350.04998438755060.34376457751-15.2575759532-21.571402270124.351661406
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 485 through 666 )
2X-RAY DIFFRACTION2chain 'A' and (resid 667 through 795 )

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