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- PDB-6kzd: Crystal structure of TRKc in complex with 3-((6-(4-aminophenyl)im... -

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Basic information

Entry
Database: PDB / ID: 6kzd
TitleCrystal structure of TRKc in complex with 3-((6-(4-aminophenyl)imidazo[1,2-a]pyrazin-3-yl)ethynyl)- N-(3-isopropyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-2- methylbenzamide
ComponentsNT-3 growth factor receptor
KeywordsTRANSFERASE / TRKc
Function / homology
Function and homology information


NTF3 activates NTRK3 signaling / Activated NTRK3 signals through PLCG1 / Signaling by NTRK3 (TRKC) / Receptor-type tyrosine-protein phosphatases / NTRK3 as a dependence receptor / neurotrophin receptor activity / neurotrophin binding / Activated NTRK3 signals through PI3K / activation of GTPase activity / positive regulation of positive chemotaxis ...NTF3 activates NTRK3 signaling / Activated NTRK3 signals through PLCG1 / Signaling by NTRK3 (TRKC) / Receptor-type tyrosine-protein phosphatases / NTRK3 as a dependence receptor / neurotrophin receptor activity / neurotrophin binding / Activated NTRK3 signals through PI3K / activation of GTPase activity / positive regulation of positive chemotaxis / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Activated NTRK3 signals through RAS / activation of protein kinase B activity / transmembrane receptor protein tyrosine kinase activity / cellular response to nerve growth factor stimulus / negative regulation of protein phosphorylation / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of MAP kinase activity / receptor protein-tyrosine kinase / positive regulation of neuron projection development / p53 binding / positive regulation of peptidyl-serine phosphorylation / nervous system development / heart development / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell differentiation / receptor complex / positive regulation of cell migration / positive regulation of protein phosphorylation / phosphorylation / axon / positive regulation of cell population proliferation / positive regulation of gene expression / ATP binding / plasma membrane
Similarity search - Function
NT-3 growth factor receptor NTRK3 / Growth factor receptor NTRK / Growth factor receptor NTRK, leucine rich repeat C-terminal / Leucine rich repeat C-terminal motif / Leucine rich repeat N-terminal domain / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Tyrosine-protein kinase, receptor class II, conserved site ...NT-3 growth factor receptor NTRK3 / Growth factor receptor NTRK / Growth factor receptor NTRK, leucine rich repeat C-terminal / Leucine rich repeat C-terminal motif / Leucine rich repeat N-terminal domain / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain / 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. / Immunoglobulin / Immunoglobulin domain / Leucine rich repeat / Immunoglobulin I-set / Immunoglobulin I-set domain / Leucine-rich repeat profile. / Leucine-rich repeat / Leucine-rich repeat domain superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / Immunoglobulin / 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 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-DZ6 / PHOSPHATE ION / NT-3 growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.708 Å
AuthorsWang, Y. / Zhang, Z.M.
CitationJournal: Eur.J.Med.Chem. / Year: 2019
Title: Design, synthesis and biological evaluation of 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methylbenzamides as potent and selective pan-tropomyosin receptor kinase (TRK) inhibitors.
Authors: Cui, S. / Wang, Y. / Wang, Y. / Tang, X. / Ren, X. / Zhang, L. / Xu, Y. / Zhang, Z. / Zhang, Z.M. / Lu, X. / Ding, K.
History
DepositionSep 23, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 9, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 27, 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: NT-3 growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,5053
Polymers35,8271
Non-polymers6792
Water5,405300
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area210 Å2
ΔGint-6 kcal/mol
Surface area14850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.695, 54.569, 108.842
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein NT-3 growth factor receptor / GP145-TrkC / Trk-C / Neurotrophic tyrosine kinase receptor type 3 / TrkC tyrosine kinase


Mass: 35826.605 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: SF file contains Friedel pairs. / Source: (gene. exp.) Homo sapiens (human) / Gene: NTRK3, TRKC / Production host: Escherichia coli (E. coli)
References: UniProt: Q16288, receptor protein-tyrosine kinase
#2: Chemical ChemComp-DZ6 / 3-[2-[6-(4-aminophenyl)imidazo[1,2-a]pyrazin-3-yl]ethynyl]-2-methyl-~{N}-[3-(4-methylpiperazin-1-yl)-5-propan-2-yl-phenyl]benzamide


Mass: 583.725 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H37N7O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 300 / 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: 2.14 Å3/Da / Density % sol: 42.59 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 0.1MMES, pH 6.0, 0.15M (NH4)2SO4, 15% PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 1, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.708→50 Å / Num. obs: 33961 / % possible obs: 99.2 % / Redundancy: 11.9 % / CC1/2: 1 / Net I/σ(I): 31.51
Reflection shellResolution: 1.71→1.77 Å / Num. unique obs: 3240 / CC1/2: 0.94

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIX1.9_1692refinement
PDB_EXTRACT3.25data extraction
HKL-2000data scaling
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.708→38.534 Å / SU ML: 0.13 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 18.74
RfactorNum. reflection% reflection
Rfree0.1836 3087 5.95 %
Rwork0.1587 --
obs0.1602 33905 80.43 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 87.58 Å2 / Biso mean: 20.7559 Å2 / Biso min: 2.59 Å2
Refinement stepCycle: final / Resolution: 1.708→38.534 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2255 0 49 300 2604
Biso mean--23.67 34.04 -
Num. residues----282
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072361
X-RAY DIFFRACTIONf_angle_d1.1033196
X-RAY DIFFRACTIONf_chiral_restr0.042343
X-RAY DIFFRACTIONf_plane_restr0.006400
X-RAY DIFFRACTIONf_dihedral_angle_d15.924882
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Highest resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.708-1.73440.245981135749
1.7344-1.76280.2333100139351
1.7628-1.79320.271887145252
1.7932-1.82580.210187146053
1.8258-1.86090.224595147554
1.8609-1.89890.2063107155857
1.8989-1.94020.203389168961
1.9402-1.98530.2244126183066
1.9853-2.0350.1764129201673
2.035-2.090.1623145220480
2.09-2.15150.2009140228083
2.1515-2.22090.2021168264896
2.2209-2.30030.17051730.145271699
2.3003-2.39240.17781692782100
2.3924-2.50120.18111902767100
2.5012-2.63310.19091512746100
2.6331-2.7980.18541842762100
2.798-3.0140.1692168275999
3.014-3.31710.2041170269098
3.3171-3.79680.17431730.14442773100
3.7968-4.78210.14531620.14092761100
4.78210.18041930.1841271399
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)
10.01070.0168-0.00120.035-0.00480.0043-0.0670.02270.00120.06380.0417-0.1607-0.0054-0.04620.01460.1104-0.002-0.07080.0887-0.00310.1584-10.4697-27.282311.6747
20.0986-0.10220.07760.1868-0.00850.1261-0.10390.0651-0.08850.01410.1847-0.1084-0.05720.00960.05950.0775-0.05970.06480.1322-0.03920.099-9.3563-27.77057.8327
30.02610.00720.02060.002-0.00240.0225-0.17960.0142-0.03860.01960.01670.1229-0.03540.0123-0.00690.1526-0.01440.03250.13380.02020.122-22.8269-18.71813.2698
40.07310.0404-0.03110.0697-0.02690.0772-0.0737-0.0073-0.0890.040.0739-0.16440.11940.0144-0.0020.0564-0.0076-0.00450.04970.00060.0798-5.2739-14.439611.9534
50.0458-0.00710.02290.14220.06040.0779-0.0151-0.07390.0323-0.00510.0371-0.02630.0044-0.0602-0.00070.0488-0.00370.01040.0740.0070.0424-9.2702-5.855415.4473
60.1667-0.10020.03230.0913-0.0390.1935-0.0654-0.13840.17840.20720.0551-0.0476-0.2043-0.0186-0.03820.03780.01640.02070.0488-0.03740.0375-9.46236.886721.6034
70.04340.03050.03120.02470.01720.04150.00360.1271-0.066-0.12830.0234-0.0290.02550.06690.00040.1230.00340.02310.1166-0.00510.0843-3.62783.95630.3633
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 528 through 557 )A528 - 557
2X-RAY DIFFRACTION2chain 'A' and (resid 558 through 578 )A558 - 578
3X-RAY DIFFRACTION3chain 'A' and (resid 579 through 594 )A579 - 594
4X-RAY DIFFRACTION4chain 'A' and (resid 595 through 652 )A595 - 652
5X-RAY DIFFRACTION5chain 'A' and (resid 653 through 731 )A653 - 731
6X-RAY DIFFRACTION6chain 'A' and (resid 732 through 816 )A732 - 816
7X-RAY DIFFRACTION7chain 'A' and (resid 817 through 837 )A817 - 837

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