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- PDB-7xaf: The crystal structure of TrkA kinase in complex with 4^6,14-dimet... -

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Basic information

Entry
Database: PDB / ID: 7xaf
TitleThe crystal structure of TrkA kinase in complex with 4^6,14-dimethyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-10-oxo-5-oxa-11,14-diaza-1(3,6)-imidazo[1,2-b]pyridazina-4(1,3)-benzenacyclo- tetradecaphan-2-yne-45-carboxamide
ComponentsHigh affinity nerve growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TrkA / Transferase Inhibitor / TRANSFERASE / 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 / Signalling to STAT3 / programmed cell death involved in cell development / mechanoreceptor differentiation / neurotrophin receptor activity ...behavioral response to formalin induced pain / neurotrophin p75 receptor binding / olfactory nerve development / response to hydrostatic pressure / TRKA activation by NGF / PLC-gamma1 signalling / Signalling to STAT3 / programmed cell death involved in cell development / mechanoreceptor differentiation / neurotrophin receptor activity / nerve growth factor receptor activity / neurotrophin binding / Sertoli cell development / GPI-linked ephrin receptor activity / nerve growth factor signaling pathway / axonogenesis involved in innervation / 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 / detection of temperature stimulus involved in sensory perception of pain / neurotrophin TRK receptor signaling pathway / response to axon injury / Signalling to RAS / neuron development / detection of mechanical stimulus involved in sensory perception of pain / peptidyl-tyrosine autophosphorylation / response to electrical stimulus / transmembrane receptor protein tyrosine kinase activity / B cell differentiation / positive regulation of synaptic transmission, glutamatergic / response to nutrient levels / positive regulation of GTPase activity / cellular response to nerve growth factor stimulus / axon guidance / receptor protein-tyrosine kinase / kinase binding / positive regulation of neuron projection development / cellular response to nicotine / peptidyl-tyrosine phosphorylation / circadian rhythm / positive regulation of angiogenesis / recycling endosome membrane / 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 / positive regulation of ERK1 and ERK2 cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / early endosome / learning or memory / receptor complex / endosome membrane / positive regulation of protein phosphorylation / response to xenobiotic stimulus / protein phosphorylation / negative regulation of cell population proliferation / axon / 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 / 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-FKT / High affinity nerve growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 3.00118200625 Å
AuthorsZhang, Z.M. / Wang, Y.J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of the First Highly Selective and Broadly Effective Macrocycle-Based Type II TRK Inhibitors that Overcome Clinically Acquired Resistance.
Authors: Wang, Z. / Wang, J. / Wang, Y. / Xiang, S. / Song, X. / Tu, Z. / Zhou, Y. / Zhang, Z.M. / Zhang, Z. / Ding, K. / Lu, X.
History
DepositionMar 17, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 1, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)34,5782
Polymers33,9071
Non-polymers6711
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13870 Å2
Unit cell
Length a, b, c (Å)52.1159, 52.1159, 228.483
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: 33907.141 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: Baculovirus expression vector pFastBac1-HM
References: UniProt: P04629, receptor protein-tyrosine kinase
#2: Chemical ChemComp-FKT / 4^6,14-dimethyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-10-oxo-5-oxa-11,14-diaza-1(3,6)-imidazo[1,2-b]pyridazina-4(1,3)-benzenacyclo-tetradecaphan-2-yne-45-carboxamide


Mass: 670.684 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H33F3N8O3 / 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: 2.64 Å3/Da / Density % sol: 53.44 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 6.2 / Details: 0.1M Na2HPO4/KH2PO4 (pH 6.2), 2M NaCl

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Data collection

DiffractionMean temperature: 104.5 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-D / Wavelength: 1.5418 Å
DetectorType: DECTRIS PILATUS 200K / Detector: PIXEL / Date: Jan 4, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 3→19.42 Å / Num. obs: 7315 / % possible obs: 100 % / Redundancy: 4.7 % / Biso Wilson estimate: 34.0744234139 Å2 / CC1/2: 0.888 / Net I/σ(I): 4.5
Reflection shellResolution: 3→3.21 Å / Num. unique obs: 2270 / CC1/2: 0.408

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Processing

Software
NameVersionClassification
PHENIX1.9_1692+SVNrefinement
CrysalisPro1.9_1692+SVNdata scaling
Cootmodel building
CrysalisProdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5H3Q

5h3q


Resolution: 3.00118200625→19.4139275078 Å / SU ML: 0.480076300413 / Cross valid method: FREE R-VALUE / σ(F): 1.36398038186 / Phase error: 27.649245432
RfactorNum. reflection% reflection
Rfree0.298970001589 729 9.96718621821 %
Rwork0.244122605039 6585 -
obs0.249636509057 7314 98.7044534413 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 21.8050788741 Å2
Refinement stepCycle: LAST / Resolution: 3.00118200625→19.4139275078 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2213 0 49 0 2262
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.003186825169322322
X-RAY DIFFRACTIONf_angle_d0.8259452441093159
X-RAY DIFFRACTIONf_chiral_restr0.0276878525387338
X-RAY DIFFRACTIONf_plane_restr0.00499369499719405
X-RAY DIFFRACTIONf_dihedral_angle_d14.109444435814
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.0012-3.23190.3548710203331460.3021555656841318X-RAY DIFFRACTION99.863574352
3.2319-3.55540.3147489713981370.2824697053211311X-RAY DIFFRACTION99.8620689655
3.5554-4.06570.3297876536581500.2445292525691316X-RAY DIFFRACTION99.2552471225
4.0657-5.10690.2401723570091500.2116071653231313X-RAY DIFFRACTION98.7846049966
5.1069-9.960.2944304450631460.2157651317831327X-RAY DIFFRACTION95.9609120521

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