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- PDB-5iui: Crystal Structure of Anaplastic Lyphoma Kinase (ALK) in complex with 4 -

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Basic information

Entry
Database: PDB / ID: 5iui
TitleCrystal Structure of Anaplastic Lyphoma Kinase (ALK) in complex with 4
ComponentsALK tyrosine kinase receptor
KeywordsTRANSFERASE / CATALYTIC DOMAIN
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-45Q / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.88 Å
AuthorsTu, C.H. / Wu, S.Y.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Pyrazolylamine Derivatives Reveal the Conformational Switching between Type I and Type II Binding Modes of Anaplastic Lymphoma Kinase (ALK).
Authors: Tu, C.H. / Lin, W.H. / Peng, Y.H. / Hsu, T. / Wu, J.S. / Chang, C.Y. / Lu, C.T. / Lyu, P.C. / Shih, C. / Jiaang, W.T. / Wu, S.Y.
History
DepositionMar 18, 2016Deposition site: RCSB / Processing site: PDBJ
Revision 1.0May 18, 2016Provider: repository / Type: Initial release
Revision 1.1Feb 19, 2020Group: Data collection / Database references / Derived calculations
Category: citation / diffrn_source / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _diffrn_source.pdbx_synchrotron_site / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Mar 20, 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

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Assembly

Deposited unit
A: ALK tyrosine kinase receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,2382
Polymers36,8331
Non-polymers4051
Water3,351186
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14060 Å2
Unit cell
Length a, b, c (Å)51.851, 57.432, 105.017
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: 36833.203 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 1084-1410 / Mutation: C1097S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALK / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Chemical ChemComp-45Q / N-[3-(4-amino-3-methylphenyl)-1H-pyrazol-5-yl]-4-[(4-methylpiperazin-1-yl)methyl]benzamide


Mass: 404.508 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H28N6O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 186 / 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: 2.12 Å3/Da / Density % sol: 42.05 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.6 / Details: 18% PEG 2000 MME, 0.1M Tris-HCl pH 8.6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL12B2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4r / Detector: CCD / Date: Feb 12, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.88→30 Å / Num. obs: 25807 / % possible obs: 97.9 % / Redundancy: 4.6 % / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.039 / Rrim(I) all: 0.087 / Χ2: 1.033 / Net I/av σ(I): 18.38 / Net I/σ(I): 10.5 / Num. measured all: 119571
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.88-1.954.60.47325800.8440.2420.5341.0699.3
1.95-2.034.70.28725590.9330.1450.3231.07599.3
2.03-2.124.70.23825520.9510.120.2681.02999
2.12-2.234.70.16625660.9770.0830.1871.02698.7
2.23-2.374.70.13625980.990.0690.1541.05898.9
2.37-2.554.80.09825560.9920.0490.111.01498.3
2.55-2.814.70.08525680.9930.0420.0951.00798.1
2.81-3.214.60.07625750.9940.0390.0861.03497.2
3.21-4.054.30.06225930.9940.0330.071.00696.8
4.05-304.60.04326600.9970.0220.0481.01794.2

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation1.88 Å23.63 Å
Translation6.56 Å23.63 Å

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Processing

Software
NameVersionClassification
HKL-2000data collection
HKL-2000data scaling
PHASER2.5.6phasing
PHENIX1.9_1692refinement
PDB_EXTRACT3.2data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.88→23.63 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 20.95
RfactorNum. reflection% reflection
Rfree0.2051 1285 4.99 %
Rwork0.1794 --
obs0.1807 25760 97.89 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 95.47 Å2 / Biso mean: 30.3485 Å2 / Biso min: 10.61 Å2
Refinement stepCycle: final / Resolution: 1.88→23.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2353 0 30 186 2569
Biso mean--32.17 35.41 -
Num. residues----303
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0052470
X-RAY DIFFRACTIONf_angle_d1.0163357
X-RAY DIFFRACTIONf_chiral_restr0.036364
X-RAY DIFFRACTIONf_plane_restr0.005437
X-RAY DIFFRACTIONf_dihedral_angle_d14.099927
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 9

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.8774-1.95260.29431380.26222679281798
1.9526-2.04140.23361570.20772708286599
2.0414-2.1490.24831480.192696284499
2.149-2.28350.21691320.18472717284999
2.2835-2.45960.18951240.16642729285399
2.4596-2.70680.19111630.17082687285098
2.7068-3.09780.20161480.17432729287798
3.0978-3.90.19591330.17142728286197
3.9-23.63140.19071420.17352802294495

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