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- PDB-5iuh: Crystal Structure of the Anaplastic Lymphoma Kinase (ALK) in comp... -

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Basic information

Entry
Database: PDB / ID: 5iuh
TitleCrystal Structure of the Anaplastic Lymphoma Kinase (ALK) in complex with 5d
ComponentsALK tyrosine kinase receptor
KeywordsTRANSFERASE / CATALYTIC DOMAIN
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 / Concanavalin A-like lectin/glucanase domain superfamily / Tyrosine protein kinases specific active-site signature. / 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-34Y / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 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 1.1Mar 20, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)37,3902
Polymers36,8331
Non-polymers5571
Water2,504139
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)52.290, 56.575, 103.049
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-34Y / 4-[(4-methylpiperazin-1-yl)methyl]-N-{3-[3-methyl-4-({[5-(propan-2-yl)-1,2-oxazol-3-yl]carbamoyl}amino)phenyl]-1H-pyrazol-5-yl}benzamide


Mass: 556.659 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H36N8O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 139 / 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: 2.07 Å3/Da / Density % sol: 40.55 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.6 / Details: 18% PEG 2000 MME, 0.1 M Tris-HCl pH 8.6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: BL15A1 / Wavelength: 1 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Dec 26, 2014
RadiationMonochromator: LN2-Cooled, Fixed-Exit Double Crystal Monochromator
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→20 Å / Num. obs: 17870 / % possible obs: 96.2 % / Redundancy: 3.8 % / Rmerge(I) obs: 0.054 / Rpim(I) all: 0.031 / Rrim(I) all: 0.063 / Χ2: 1.034 / Net I/av σ(I): 21.974 / Net I/σ(I): 14.1 / Num. measured all: 67092
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.1-2.173.70.35116590.8950.2040.4081.00191.9
2.17-2.263.60.27116730.9120.1590.3151.02391.4
2.26-2.363.60.19416580.9590.1130.2260.99691
2.36-2.493.50.14817060.9730.0880.1731.00793
2.49-2.643.50.11217730.9850.0670.1311.04697.3
2.64-2.853.60.09118240.990.0540.1061.0699.2
2.85-3.133.90.06318600.9960.0360.0731.00599.9
3.13-3.594.20.04418580.9980.0240.051.014100
3.59-4.5140.03718790.9970.0210.0431.08199.3
4.51-203.90.03119800.9980.0180.0361.08798.8

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation2.09 Å19.53 Å
Translation6.54 Å19.53 Å

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-2000data collection
HKL-2000data scaling
PHASER2.5.6model building
PDB_EXTRACT3.2data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→19.526 Å / SU ML: 0.18 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 20.8 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2208 877 4.92 %
Rwork0.1811 16956 -
obs0.183 17833 96.08 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 97.39 Å2 / Biso mean: 34.4546 Å2 / Biso min: 15.01 Å2
Refinement stepCycle: final / Resolution: 2.1→19.526 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2222 0 41 139 2402
Biso mean--35.94 37.4 -
Num. residues----285
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0052323
X-RAY DIFFRACTIONf_angle_d0.8763153
X-RAY DIFFRACTIONf_chiral_restr0.038343
X-RAY DIFFRACTIONf_plane_restr0.004407
X-RAY DIFFRACTIONf_dihedral_angle_d12.753864
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 6

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.0948-2.22590.24121300.19872615274591
2.2259-2.39750.22671380.19022630276891
2.3975-2.63820.22891140.18472805291996
2.6382-3.01880.24451750.19122881305699
3.0188-3.79880.23021620.181929563118100
3.7988-19.52670.19831580.17023069322799

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