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- PDB-4anl: Structure of G1269A Mutant Anaplastic Lymphoma Kinase -

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Basic information

Entry
Database: PDB / ID: 4anl
TitleStructure of G1269A Mutant Anaplastic Lymphoma Kinase
ComponentsALK TYROSINE KINASE RECEPTOR
KeywordsTRANSFERASE / CRIZOTINIB
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 / phosphorylation / positive regulation of dendrite development / regulation of neuron differentiation / peptidyl-tyrosine autophosphorylation / Signaling by ALK / response to stress / adult behavior / neuron development / negative regulation of lipid catabolic process / energy homeostasis / transmembrane receptor protein tyrosine kinase activity / cell surface receptor protein tyrosine kinase signaling pathway / hippocampus development / positive regulation of NF-kappaB transcription factor activity / receptor protein-tyrosine kinase / 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. / Low-density lipoprotein receptor domain class A / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / 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. / Low-density lipoprotein receptor domain class A / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / 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
ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.7 Å
AuthorsMcTigue, M. / Deng, Y. / Liu, W. / Brooun, A.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Design of Potent and Selective Inhibitors to Overcome Clinical Anaplastic Lymphoma Kinase Mutations Resistant to Crizotinib.
Authors: Huang, Q. / Johnson, T.W. / Bailey, S. / Brooun, A. / Bunker, K.D. / Burke, B.J. / Collins, M.R. / Cook, A.S. / Cui, J.J. / Dack, K.N. / Deal, J.G. / Deng, Y. / Dinh, D. / Engstrom, L.D. / ...Authors: Huang, Q. / Johnson, T.W. / Bailey, S. / Brooun, A. / Bunker, K.D. / Burke, B.J. / Collins, M.R. / Cook, A.S. / Cui, J.J. / Dack, K.N. / Deal, J.G. / Deng, Y. / Dinh, D. / Engstrom, L.D. / He, M. / Hoffman, J. / Hoffman, R.L. / Johnson, P.S. / Kania, R.S. / Lam, H. / Lam, J.L. / Le, P.T. / Li, Q. / Lingardo, L. / Liu, W. / Lu, M.W. / Mctigue, M. / Palmer, C.L. / Richardson, P.F. / Sach, N.W. / Shen, H. / Smeal, T. / Smith, G.L. / Stewart, A.E. / Timofeevski, S. / Tsaparikos, K. / Wang, H. / Zhu, H. / Zhu, J. / Zou, H.Y. / Edwards, M.P.
History
DepositionMar 20, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 27, 2013Provider: repository / Type: Initial release
Revision 1.1Mar 19, 2014Group: Database references
Revision 1.2May 8, 2019Group: Data collection / Experimental preparation / Other
Category: database_PDB_rev / database_PDB_rev_record ...database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.method / _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval
Revision 1.3Dec 20, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ALK TYROSINE KINASE RECEPTOR


Theoretical massNumber of molelcules
Total (without water)38,6101
Polymers38,6101
Non-polymers00
Water4,936274
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.836, 57.592, 105.151
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 / CD246


Mass: 38610.148 Da / Num. of mol.: 1 / Fragment: KINASE, RESIDUES 1093-1411 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBAC1 / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 274 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, GLY 1269 TO ALA

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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: 2.18 Å3/Da / Density % sol: 43.54 % / Description: NONE
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: CRYSTALS WERE GROWN BY THE HANGING DROP VAPOR DIFFUSION METHOD AT 13 DEGRESS CELCIUS BY MIXING 2 MICROLITERS OF PROTEIN SOLUTION WITH A RESERVOIR SOLUTION CONTAINING: 19% (W/V) PEG 3350, 0.1 ...Details: CRYSTALS WERE GROWN BY THE HANGING DROP VAPOR DIFFUSION METHOD AT 13 DEGRESS CELCIUS BY MIXING 2 MICROLITERS OF PROTEIN SOLUTION WITH A RESERVOIR SOLUTION CONTAINING: 19% (W/V) PEG 3350, 0.1 M TRIS PH 8.5, 0.2 M LITHIUM SULFATE, AND 0.1 (W/V) BETA-OCTYLGLCOSIDE

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Data collection

DiffractionMean temperature: 87 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 17, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.7→105.15 Å / Num. obs: 35264 / % possible obs: 99.5 % / Observed criterion σ(I): 2 / Redundancy: 6.4 % / Biso Wilson estimate: 24.4 Å2 / Rmerge(I) obs: 0.04 / Net I/σ(I): 24.5
Reflection shellResolution: 1.7→1.79 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.46 / Mean I/σ(I) obs: 3.5 / % possible all: 98.3

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Processing

Software
NameVersionClassification
CNX2005refinement
autoPROCdata reduction
SCALAdata scaling
CNXphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 2XP2

2xp2


Resolution: 1.7→52.58 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 1141278.31 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.216 1054 3 %RANDOM
Rwork0.202 ---
obs-35145 99.3 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 50.345 Å2 / ksol: 0.372006 e/Å3
Displacement parametersBiso mean: 27.6 Å2
Baniso -1Baniso -2Baniso -3
1--3.69 Å20 Å20 Å2
2---0.72 Å20 Å2
3---4.41 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.23 Å0.19 Å
Luzzati d res low-5 Å
Luzzati sigma a0.16 Å0.12 Å
Refinement stepCycle: LAST / Resolution: 1.7→52.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2305 0 0 274 2579
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.004
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg0.8
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d18.8
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.65
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.321.5
X-RAY DIFFRACTIONc_mcangle_it2.092
X-RAY DIFFRACTIONc_scbond_it2.242
X-RAY DIFFRACTIONc_scangle_it3.382.5
LS refinement shellResolution: 1.7→1.81 Å / Rfactor Rfree error: 0.021 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.271 164 2.9 %
Rwork0.255 5525 -
obs--98.1 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2DNA-RNA_REP.PARAMDNA-RNA.TOP
X-RAY DIFFRACTION3WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION4ION.PARAMION.TOP

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