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- PDB-4fod: Crystal structure of human anaplastic lymphoma kinase in complex ... -

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Basic information

Entry
Database: PDB / ID: 4fod
TitleCrystal structure of human anaplastic lymphoma kinase in complex with acyliminobenzimidazole inhibitor 36
ComponentsALK tyrosine kinase receptor
KeywordsTransferase/Inhibitor / receptor tyrosine kinase / inhibitor / crizotinib / neuroblastoma / CD246 / phosphotransferase / NPM-ALK / EML4-ALK / Transferase-Inhibitor complex
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 / positive regulation of dendrite development / regulation of neuron differentiation / Signaling by ALK / adult behavior / neuron development / negative regulation of lipid catabolic process / phosphorylation / peptidyl-tyrosine autophosphorylation / cell surface receptor protein tyrosine kinase signaling pathway / energy homeostasis / transmembrane receptor protein tyrosine kinase activity / hippocampus development / receptor protein-tyrosine kinase / Signaling by ALK fusions and activated point mutants / heparin binding / positive regulation of NF-kappaB transcription factor activity / regulation of cell population proliferation / protein tyrosine kinase activity / regulation of apoptotic process / protein autophosphorylation / receptor complex / signal transduction / protein-containing complex / extracellular exosome / ATP binding / identical protein binding / plasma membrane
Similarity search - Function
Glycine rich protein / MAM domain, meprin/A5/mu / MAM domain / MAM domain profile. / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / : ...Glycine rich protein / MAM domain, meprin/A5/mu / MAM domain / MAM domain profile. / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / : / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-0UV / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2 Å
AuthorsWhittington, D.A. / Epstein, L.F. / Chen, H.
CitationJournal: J.Med.Chem. / Year: 2012
Title: The Discovery and Optimization of a Novel Class of Potent, Selective, and Orally Bioavailable Anaplastic Lymphoma Kinase (ALK) Inhibitors with Potential Utility for the Treatment of Cancer.
Authors: Lewis, R.T. / Bode, C.M. / Choquette, D.M. / Potashman, M. / Romero, K. / Stellwagen, J.C. / Teffera, Y. / Moore, E. / Whittington, D.A. / Chen, H. / Epstein, L.F. / Emkey, R. / Andrews, P.S. ...Authors: Lewis, R.T. / Bode, C.M. / Choquette, D.M. / Potashman, M. / Romero, K. / Stellwagen, J.C. / Teffera, Y. / Moore, E. / Whittington, D.A. / Chen, H. / Epstein, L.F. / Emkey, R. / Andrews, P.S. / Yu, V.L. / Saffran, D.C. / Xu, M. / Drew, A. / Merkel, P. / Szilvassy, S. / Brake, R.L.
History
DepositionJun 20, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 11, 2012Provider: repository / Type: Initial release
Revision 1.1Aug 15, 2012Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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

Downloads & links

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Assembly

Deposited unit
A: ALK tyrosine kinase receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2383
Polymers37,5681
Non-polymers6702
Water4,522251
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.717, 57.700, 105.939
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 ALK tyrosine kinase receptor / Anaplastic lymphoma kinase


Mass: 37568.133 Da / Num. of mol.: 1 / Fragment: Kinase domain, unp residues 1078-1410 / Mutation: C1097S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Chemical ChemComp-0UV / 4-fluoro-N-{(2E)-6-{[4-(2-hydroxypropan-2-yl)piperidin-1-yl]methyl}-1-[cis-4-(propan-2-ylcarbamoyl)cyclohexyl]-1,3-dihydro-2H-benzimidazol-2-ylidene}benzamide


Mass: 577.733 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H44FN5O3
#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.: 251 / 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: 2.1 Å3/Da / Density % sol: 41.53 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 30% PEG 5000 monomethyl ether, 200 mM ammonium sulfate, 2 mM dithiothreitol, 100 mM sodium cacodylate (pH 6.5), VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97857 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Oct 30, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. all: 22378 / Num. obs: 22266 / % possible obs: 99.5 % / Observed criterion σ(I): -3 / Redundancy: 4.1 % / Biso Wilson estimate: 24.6 Å2 / Rmerge(I) obs: 0.088 / Χ2: 1.038 / Net I/σ(I): 6.6
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2-2.073.90.55721631.011199.2
2.07-2.1540.40821811.003199
2.15-2.254.10.31821701.045198.9
2.25-2.374.10.24521771.093198.7
2.37-2.524.10.18722181.041199.6
2.52-2.714.20.13921921.022199.8
2.71-2.994.20.09622351.0181100
2.99-3.424.20.07722521.0111100
3.42-4.314.20.0522771.0841100
4.31-503.90.03224011.053199.4

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.11data extraction
HKL-2000data reduction
HKL-2000data scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2→36.2 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.937 / WRfactor Rfree: 0.2093 / WRfactor Rwork: 0.172 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8603 / SU B: 3.914 / SU ML: 0.11 / SU R Cruickshank DPI: 0.1941 / SU Rfree: 0.1654 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.194 / ESU R Free: 0.165 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2211 1313 6 %RANDOM
Rwork0.177 ---
obs0.1796 21980 99.45 %-
all-22102 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 99.6 Å2 / Biso mean: 26.7653 Å2 / Biso min: 10.87 Å2
Baniso -1Baniso -2Baniso -3
1--0.12 Å20 Å20 Å2
2--0.12 Å20 Å2
3---0 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.165 Å0.194 Å
Refinement stepCycle: LAST / Resolution: 2→36.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2423 0 48 251 2722
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.022579
X-RAY DIFFRACTIONr_bond_other_d0.0010.021787
X-RAY DIFFRACTIONr_angle_refined_deg1.2122.0113507
X-RAY DIFFRACTIONr_angle_other_deg0.863.0054270
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3485305
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.29823.761109
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.98915419
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.21517
X-RAY DIFFRACTIONr_chiral_restr0.0720.2384
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212790
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02499
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.301 91 -
Rwork0.252 1362 -
all-1453 -
obs--99.38 %

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