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

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Basic information

Entry
Database: PDB / ID: 4foc
TitleCrystal structure of human anaplastic lymphoma kinase in complex with acyliminobenzimidazole inhibitor 2
ComponentsALK tyrosine kinase receptor
KeywordsTransferase/Inhibitor / receptor tyrosine kinase / inhibitor / crizotinib / neuroblastoma / CD246 / phosphotransferase / NPM-ALK / EML4-ALK / in situ proteolysis / Transferase-Inhibitor complex
Function / homology
Function and homology information


response to environmental enrichment / 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 / receptor signaling protein tyrosine kinase activator activity / regulation of dopamine receptor signaling pathway ...response to environmental enrichment / 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 / receptor signaling protein tyrosine kinase activator activity / regulation of dopamine receptor signaling pathway / ALK mutants bind TKIs / swimming behavior / positive regulation of dendrite development / regulation of neuron differentiation / adult behavior / Signaling by ALK / Signaling by ALK fusions and activated point mutants / neuron development / Nuclear events stimulated by ALK signaling in cancer / negative regulation of lipid catabolic process / energy homeostasis / peptidyl-tyrosine autophosphorylation / transmembrane receptor protein tyrosine kinase activity / hippocampus development / receptor protein-tyrosine kinase / cell surface receptor protein tyrosine kinase signaling pathway / 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 / phosphorylation / 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. / Tyrosine-protein kinase, catalytic domain ...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. / Concanavalin A-like lectin/glucanase domain superfamily / 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 / 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-0UU / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.7 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 1.2Feb 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

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Assembly

Deposited unit
A: ALK tyrosine kinase receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,5312
Polymers40,0561
Non-polymers4751
Water5,729318
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.686, 57.505, 105.432
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: 40055.977 Da / Num. of mol.: 1 / Fragment: Kinase domain, unp residues 1058-1410 / 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-0UU / methyl cis-4-[2-(benzoylamino)-6-(piperidin-1-ylmethyl)-1H-benzimidazol-1-yl]cyclohexanecarboxylate


Mass: 474.595 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H34N4O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 318 / 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: 1.96 Å3/Da / Density % sol: 37.11 %
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 MES (pH 6.5) - 1:200 (w/w) chymotrypsin:ALK, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Feb 7, 2009
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.7→50 Å / Num. all: 35475 / Num. obs: 35440 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 4 % / Biso Wilson estimate: 23.6 Å2 / Rmerge(I) obs: 0.063 / Χ2: 1.113 / Net I/σ(I): 9.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.7-1.764.10.64834821.0431100
1.76-1.834.10.47334671.0721100
1.83-1.914.10.32735281.0891100
1.91-2.024.10.21534701.051100
2.02-2.144.10.1435361.0731100
2.14-2.314.10.10135031.1051100
2.31-2.544.10.07735141.21100
2.54-2.9140.07235781.179199.9
2.91-3.6640.05536011.1841100
3.66-503.80.03137611.129199.5

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.11data extraction
HKL-2000data reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.7→50 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.949 / WRfactor Rfree: 0.2309 / WRfactor Rwork: 0.1886 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.8562 / SU B: 2.211 / SU ML: 0.074 / SU R Cruickshank DPI: 0.1122 / SU Rfree: 0.1102 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.112 / ESU R Free: 0.11 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2252 1772 5 %RANDOM
Rwork0.1891 ---
obs0.1908 35324 99.92 %-
all-35352 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 78.81 Å2 / Biso mean: 27.4317 Å2 / Biso min: 11.42 Å2
Baniso -1Baniso -2Baniso -3
1-0.05 Å20 Å20 Å2
2---0.45 Å20 Å2
3---0.4 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.11 Å0.112 Å
Refinement stepCycle: LAST / Resolution: 1.7→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2333 0 35 318 2686
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.022429
X-RAY DIFFRACTIONr_bond_other_d0.0010.021697
X-RAY DIFFRACTIONr_angle_refined_deg1.1951.993294
X-RAY DIFFRACTIONr_angle_other_deg0.863.0034088
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1235293
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.19623.738107
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.40915405
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.9881517
X-RAY DIFFRACTIONr_chiral_restr0.0710.2356
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212661
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02481
LS refinement shellResolution: 1.7→1.744 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.319 138 -
Rwork0.281 2239 -
all-2377 -
obs--99.92 %

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