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- PDB-5ftq: Crystal structure of the ALK kinase domain in complex with Cmpd 17 -

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Basic information

Entry
Database: PDB / ID: 5ftq
TitleCrystal structure of the ALK kinase domain in complex with Cmpd 17
ComponentsALK TYROSINE KINASE RECEPTOR
KeywordsTRANSFERASE / KINASE INHIBITORS / CANCER / DRUG DISCOVERY / ALK / TRK / ROS1 / ANAPLASTIC LARGE CELL LYMPHOMA (ALCL) / NON SMALL CELL LARGE CANCER (NSCLC) / NEUROBLASTOMA / COLORECTAL CANCER (CRC)
Function / homology
Function and homology information


ASP-3026-resistant ALK mutants / NVP-TAE684-resistant ALK mutants / alectinib-resistant ALK mutants / brigatinib-resistant ALK mutants / ceritinib-resistant ALK mutants / crizotinib-resistant ALK mutants / lorlatinib-resistant ALK mutants / MDK and PTN in ALK signaling / receptor signaling protein tyrosine kinase activator activity / regulation of dopamine receptor signaling pathway ...ASP-3026-resistant ALK mutants / NVP-TAE684-resistant ALK mutants / alectinib-resistant ALK mutants / brigatinib-resistant ALK mutants / ceritinib-resistant ALK mutants / crizotinib-resistant ALK mutants / lorlatinib-resistant ALK mutants / MDK and PTN in ALK signaling / receptor signaling protein tyrosine kinase activator activity / regulation of dopamine receptor signaling pathway / response to environmental enrichment / ALK mutants bind TKIs / swimming behavior / regulation of neuron differentiation / positive regulation of dendrite development / Signaling by ALK / phosphorylation / response to stress / adult behavior / neuron development / negative regulation of lipid catabolic process / peptidyl-tyrosine autophosphorylation / energy homeostasis / transmembrane receptor protein tyrosine kinase activity / cell surface receptor protein tyrosine kinase signaling pathway / hippocampus development / 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 / positive regulation of NF-kappaB transcription factor activity / Signaling by ALK fusions and activated point mutants / heparin binding / regulation of cell population proliferation / protein autophosphorylation / protein tyrosine kinase activity / regulation of apoptotic process / receptor complex / signal transduction / protein-containing complex / extracellular exosome / ATP binding / identical protein binding / plasma membrane
Similarity search - Function
: / ALK/LTK, Glycine-rich domain / MAM domain, meprin/A5/mu / MAM domain / MAM domain profile. / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily ...: / ALK/LTK, Glycine-rich domain / MAM domain, meprin/A5/mu / MAM domain / MAM domain profile. / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / : / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Concanavalin A-like lectin/glucanase domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / 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-U4W / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsBossi, R. / Canevari, G. / Fasolini, M. / Menichincheri, M. / Ardini, E. / Magnaghi, P. / Avanzi, N. / Banfi, P. / Buffa, L. / Ceriani, L. ...Bossi, R. / Canevari, G. / Fasolini, M. / Menichincheri, M. / Ardini, E. / Magnaghi, P. / Avanzi, N. / Banfi, P. / Buffa, L. / Ceriani, L. / Colombo, M. / Corti, L. / Donati, D. / Felder, E. / Fiorelli, C. / Fiorentini, F. / Galvani, A. / Isacchi, A. / Lombardi Borgia, A. / Marchionni, C. / Nesi, M. / Orrenius, C. / Panzeri, A. / Perrone, E. / Pesenti, E. / Rusconi, L. / Saccardo, M.B. / Vanotti, E. / Orsini, P.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Discovery of Entrectinib: A New 3-Aminoindazole as a Potent Anaplastic Lymphoma Kinase (Alk), C-Ros Oncogene 1 Kinase (Ros1), and Pan-Tropomyosin Receptor Kinases (Pan-Trks) Inhibitor.
Authors: Menichincheri, M. / Ardini, E. / Magnaghi, P. / Avanzi, N. / Banfi, P. / Bossi, R.T. / Buffa, L. / Canevari, G. / Ceriani, L. / Colombo, M. / Corti, L. / Donati, D. / Fasolini, M. / Felder, ...Authors: Menichincheri, M. / Ardini, E. / Magnaghi, P. / Avanzi, N. / Banfi, P. / Bossi, R.T. / Buffa, L. / Canevari, G. / Ceriani, L. / Colombo, M. / Corti, L. / Donati, D. / Fasolini, M. / Felder, E.R. / Fiorelli, C. / Fiorentini, F. / Galvani, A. / Isacchi, A. / Borgia, A.L. / Marchionni, C. / Nesi, M. / Orrenius, C. / Panzeri, A. / Pesenti, E. / Rusconi, L. / Saccardo, B.M. / Vanotti, E. / Perrone, E. / Orsini, P.
History
DepositionJan 14, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 6, 2016Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2016Group: Database references
Revision 1.2Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ALK TYROSINE KINASE RECEPTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,0013
Polymers35,3351
Non-polymers6672
Water6,467359
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)52.254, 58.312, 104.882
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein ALK TYROSINE KINASE RECEPTOR / ANAPLASTIC LYMPHOMA KINASE / ALK


Mass: 35334.617 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, UNP RESIDUES 1094-1407
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PVL-GST-ALK-KD / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Chemical ChemComp-U4W / N-[5-(3,5-DIFLUOROBENZYL)-1H-INDAZOL-3-YL]-2-[(4-HYDROXYCYCLOHEXYL)AMINO]-4-(4-METHYLPIPERAZIN-1-YL) BENZAMIDE


Mass: 574.664 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H36F2N6O2
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 359 / 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: 2.28 Å3/Da / Density % sol: 46 % / Description: NONE
Crystal growDetails: 18% PEG3350, 0.1 M TRIS/HCL PH 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.0723
DetectorType: ADSC CCD / Detector: CCD / Date: Dec 6, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0723 Å / Relative weight: 1
ReflectionResolution: 1.7→58.32 Å / Num. obs: 34703 / % possible obs: 97 % / Observed criterion σ(I): 2 / Redundancy: 4.2 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 19.6
Reflection shellResolution: 1.7→1.79 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.28 / Mean I/σ(I) obs: 4.1 / % possible all: 96.5

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2XBA

2xba


Resolution: 1.7→50.96 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.942 / Cross valid method: THROUGHOUT / ESU R: 0.107 / ESU R Free: 0.111 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.21995 1772 5.1 %RANDOM
Rwork0.17301 ---
obs0.17543 32905 96.3 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 25.786 Å2
Baniso -1Baniso -2Baniso -3
1--0.05 Å20 Å20 Å2
2---0.32 Å20 Å2
3---0.37 Å2
Refinement stepCycle: LAST / Resolution: 1.7→50.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2311 0 48 359 2718
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0230.022438
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.2151.9973311
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6385297
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.85323.738107
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.26715405
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.5331517
X-RAY DIFFRACTIONr_chiral_restr0.1490.2359
X-RAY DIFFRACTIONr_gen_planes_refined0.0130.0211853
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.7→1.744 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.342 103 -
Rwork0.28 2417 -
obs--96 %

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