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- PDB-2xp2: Structure of the Human Anaplastic Lymphoma Kinase in Complex with... -

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Basic information

Entry
Database: PDB / ID: 2xp2
TitleStructure of the Human Anaplastic Lymphoma Kinase in Complex with Crizotinib (PF-02341066)
ComponentsTYROSINE-PROTEIN KINASE RECEPTOR
KeywordsTRANSFERASE / CRIZOTINIB
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 / membrane / 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-VGH / Tyrosine-protein kinase receptor / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsMcTigue, M. / Deng, Y. / Liu, W. / Brooun, A. / Timofeevski, S. / Marrone, T. / Cui, J.J.
CitationJournal: J.Med.Chem / Year: 2011
Title: Structure Based Drug Design of Crizotinib (Pf-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal-Epithelial Transition Factor (C-met) Kinase and Anaplastic Lymphoma Kinase (Alk).
Authors: Cui, J.J. / Tran-Dube, M. / Shen, H. / Nambu, M. / Kung, P.P. / Pairish, M. / Jia, L. / Meng, J. / Funk, L. / Botrous, I. / Mctigue, M. / Grodsky, N. / Ryan, K. / Padrique, E. / Alton, G. / ...Authors: Cui, J.J. / Tran-Dube, M. / Shen, H. / Nambu, M. / Kung, P.P. / Pairish, M. / Jia, L. / Meng, J. / Funk, L. / Botrous, I. / Mctigue, M. / Grodsky, N. / Ryan, K. / Padrique, E. / Alton, G. / Timofeevski, S. / Yamazaki, S. / Li, Q. / Zou, H. / Christensen, J. / Mroczkowski, B. / Bender, S. / Kania, R.S. / Edwards, M.P.
History
DepositionAug 24, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 15, 2010Provider: repository / Type: Initial release
Revision 1.1Sep 28, 2011Group: Database references / Structure summary / Version format compliance
Revision 1.2May 8, 2019Group: Data collection / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval
Revision 1.3May 15, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.method
Revision 1.4Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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: TYROSINE-PROTEIN KINASE RECEPTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,3602
Polymers36,9091
Non-polymers4501
Water3,009167
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.633, 57.086, 104.709
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 TYROSINE-PROTEIN KINASE RECEPTOR / ANAPLASTIC LYMPHOMA KINASE


Mass: 36909.355 Da / Num. of mol.: 1 / Fragment: TYROSINE KINASE DOMAIN, RESIDUES 105-423
Source method: isolated from a genetically manipulated source
Details: NONPHOSPHORYLATED / Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBAC / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: B6EXY4, UniProt: Q9UM73*PLUS, receptor protein-tyrosine kinase
#2: Chemical ChemComp-VGH / 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyridin-2-amine / CRIZOTINIB / Crizotinib


Mass: 450.337 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H22Cl2FN5O / Comment: medication, anticancer, inhibitor*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 167 / 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: 1.99 Å3/Da / Density % sol: 38.5 % / Description: NONE
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: CO-CRYSTALS OF ALK KINASE DOMAIN WITH PF-02341066 WERE OBTAINED AT 13 DEGREES C BY USING HANGING-DROP VAPOR-DIFFUSION. 0.5 MICROLITERS OF 1:3 MOLAR RATIO OF 14.9 MG/ML PROTEIN SOLUTION TO ...Details: CO-CRYSTALS OF ALK KINASE DOMAIN WITH PF-02341066 WERE OBTAINED AT 13 DEGREES C BY USING HANGING-DROP VAPOR-DIFFUSION. 0.5 MICROLITERS OF 1:3 MOLAR RATIO OF 14.9 MG/ML PROTEIN SOLUTION TO PF02341066 WAS MIXED WITH 0.5 MICROLITERS OF RESERVOIR SOLUTION CONTAINING 7-10% (W/V) MEPEG 5K, 0.1M MES, PH6.0-6.5 AND 0.15M (NH4)2SO4.

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Data collection

DiffractionMean temperature: 80 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1
DetectorType: ADSC CCD / Detector: CCD / Date: Mar 26, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.86→104.71 Å / Num. obs: 24837 / % possible obs: 92.8 % / Observed criterion σ(I): 2 / Redundancy: 5.7 % / Biso Wilson estimate: 18.8 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 16
Reflection shellResolution: 1.86→1.96 Å / Redundancy: 2.3 % / Rmerge(I) obs: 0.33 / Mean I/σ(I) obs: 2 / % possible all: 64

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Processing

Software
NameVersionClassification
CNS2005refinement
XDSdata reduction
SCALAdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2WGJ

2wgj


Resolution: 1.9→36.76 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 1420278.56 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.252 1147 4.8 %RANDOM
Rwork0.207 ---
obs0.207 23821 95 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 55.504 Å2 / ksol: 0.394755 e/Å3
Displacement parametersBiso mean: 37 Å2
Baniso -1Baniso -2Baniso -3
1--4.18 Å20 Å20 Å2
2---6.55 Å20 Å2
3---10.73 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.28 Å0.22 Å
Luzzati d res low-5 Å
Luzzati sigma a0.26 Å0.23 Å
Refinement stepCycle: LAST / Resolution: 1.9→36.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2262 0 30 167 2459
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
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_d18.5
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.69
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.561.5
X-RAY DIFFRACTIONc_mcangle_it2.52
X-RAY DIFFRACTIONc_scbond_it2.392
X-RAY DIFFRACTIONc_scangle_it3.612.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 1.9→2.02 Å / Rfactor Rfree error: 0.028 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.332 142 4.7 %
Rwork0.286 2906 -
obs--74.3 %
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
X-RAY DIFFRACTION5UNL.PARAMUNL.TOP

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