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- PDB-2xb7: Structure of Human Anaplastic Lymphoma Kinase in complex with NVP... -

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Basic information

Entry
Database: PDB / ID: 2xb7
TitleStructure of Human Anaplastic Lymphoma Kinase in complex with NVP- TAE684
ComponentsALK TYROSINE KINASE RECEPTOR
KeywordsTRANSFERASE / ATP-BINDING / RECEPTOR
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 ...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 / neuron development / Signaling by ALK fusions and activated point mutants / 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 / regulation of cell population proliferation / positive regulation of NF-kappaB transcription factor activity / 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-GUI / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsBossi, R.T. / Saccardo, M.B. / Ardini, E. / Menichincheri, M. / Rusconi, L. / Magnaghi, P. / Orsini, P. / Fogliatto, G. / Bertrand, J.A.
CitationJournal: Biochemistry / Year: 2010
Title: Crystal Structures of Anaplastic Lymphoma Kinase in Complex with ATP Competitive Inhibitors.
Authors: Bossi, R.T. / Saccardo, M.B. / Ardini, E. / Menichincheri, M. / Rusconi, L. / Magnaghi, P. / Orsini, P. / Avanzi, N. / Borgia, A.L. / Nesi, M. / Bandiera, T. / Fogliatto, G. / Bertrand, J.A.
History
DepositionApr 8, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 28, 2010Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance

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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)35,9492
Polymers35,3351
Non-polymers6141
Water1,18966
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.781, 57.307, 105.157
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: 35334.617 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 1094-1407
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PVL-GST-ALK-KD / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / Strain (production host): SF9
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Chemical ChemComp-GUI / 5-CHLORO-N-[2-METHOXY-4-[4-(4-METHYLPIPERAZIN-1-YL)PIPERIDIN-1-YL]PHENYL]-N'-(2-PROPAN-2-YLSULFONYLPHENYL)PYRIMIDINE-2,4-DIAMINE / 4-[1-(4-{[5-CHLORO-4-({2-[(1-METHYLETHYL)SULFONYL]PHENYL}AMINO)PYRIMIDIN-2-YL]AMINO}-3-METHOXYPHENYL)PIPERIDIN-4-YL]-1-METHYLPIPERAZIN-1-IUM


Mass: 614.202 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H40ClN7O3S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 66 / 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: 2.2 Å3/Da / Density % sol: 44 % / Description: NONE
Crystal growpH: 8.5 / Details: 18% PEG3350, 0.1 M TRIS/HCL PH 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-3 / Wavelength: 0.931
DetectorType: ADSC CCD / Detector: CCD / Date: May 4, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.931 Å / Relative weight: 1
ReflectionResolution: 2.5→57.26 Å / Num. obs: 11104 / % possible obs: 98.3 % / Observed criterion σ(I): 0 / Redundancy: 4.3 % / Biso Wilson estimate: 40.5 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 6.9
Reflection shellResolution: 2.5→2.64 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.43 / Mean I/σ(I) obs: 1.7 / % possible all: 99.5

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Processing

Software
NameClassification
CNSrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: INTERNAL STRUCTURE OF IGF-1R

Resolution: 2.5→29.9 Å / Rfactor Rfree error: 0.01 / Data cutoff high absF: 1138548.12 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.243 552 5 %RANDOM
Rwork0.195 ---
obs0.195 11079 97.7 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 37.3474 Å2 / ksol: 0.361769 e/Å3
Displacement parametersBiso mean: 34 Å2
Baniso -1Baniso -2Baniso -3
1-0.16 Å20 Å20 Å2
2---4.03 Å20 Å2
3---3.87 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.35 Å0.27 Å
Luzzati d res low-5 Å
Luzzati sigma a0.41 Å0.27 Å
Refinement stepCycle: LAST / Resolution: 2.5→29.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2252 0 42 66 2360
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.009
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_deg1.2
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d20.3
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.9
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.421.5
X-RAY DIFFRACTIONc_mcangle_it2.432
X-RAY DIFFRACTIONc_scbond_it2.112
X-RAY DIFFRACTIONc_scangle_it3.132.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 2.5→2.66 Å / Rfactor Rfree error: 0.039 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.335 73 4 %
Rwork0.267 1747 -
obs--99.2 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3GUI.PARGUI.TOP

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