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- PDB-5aaa: Structure of L1198F Mutant Human Anaplastic Lymphoma Kinase in Co... -

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Basic information

Entry
Database: PDB / ID: 5aaa
TitleStructure of L1198F Mutant Human Anaplastic Lymphoma Kinase in Complex with Crizotinib
ComponentsALK TYROSINE KINASE RECEPTOR
KeywordsTRANSFERASE / RECEPTOR TYROSINE KINASE / ANAPLASTIC LYMPHOMA KINASE / INHIBITOR / MUTANT
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 / regulation of neuron differentiation / positive regulation of dendrite development / peptidyl-tyrosine autophosphorylation / Signaling by ALK / adult behavior / response to stress / 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 / receptor protein-tyrosine kinase / : / Signaling by ALK fusions and activated point mutants / regulation of cell population proliferation / heparin binding / 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
Chem-VGH / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.73 Å
AuthorsMcTigue, M. / Deng, Y. / Liu, W. / Brooun, A. / Stewart, A.
CitationJournal: N.Engl.J.Med. / Year: 2016
Title: Resensitization to Crizotinib by the Lorlatinib Alk Resistance Mutation L1198F.
Authors: Shaw, A.T. / Friboulet, L. / Leshchiner, I. / Gainor, J.F. / Bergqvist, S. / Brooun, A. / Burke, B.J. / Deng, Y. / Liu, W. / Dardaei, L. / Frias, R.L. / Schultz, K.R. / Logan, J. / James, L. ...Authors: Shaw, A.T. / Friboulet, L. / Leshchiner, I. / Gainor, J.F. / Bergqvist, S. / Brooun, A. / Burke, B.J. / Deng, Y. / Liu, W. / Dardaei, L. / Frias, R.L. / Schultz, K.R. / Logan, J. / James, L.P. / Smeal, T. / Timofeevski, S. / Katayama, R. / Iafrate, A.J. / Le, L. / Mctigue, M. / Getz, G. / Johnson, T.W. / Engelman, J.A.
History
DepositionJul 23, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 8, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 14, 2017Group: Data collection / Other / Category: diffrn_source / pdbx_database_status
Item: _diffrn_source.pdbx_wavelength / _pdbx_database_status.status_code_sf
Revision 1.2Jul 4, 2018Group: Data collection / Category: diffrn_radiation_wavelength / Item: _diffrn_radiation_wavelength.wavelength
Revision 1.3May 8, 2019Group: Data collection / Experimental preparation
Category: database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow
Item: _exptl_crystal_grow.method / _exptl_crystal_grow.temp
Revision 1.4Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / software / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name / _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: ALK TYROSINE KINASE RECEPTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,3942
Polymers36,9431
Non-polymers4501
Water4,089227
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.471, 57.281, 104.702
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


Mass: 36943.371 Da / Num. of mol.: 1 / Fragment: TYROSINE KINASE DOMAIN, UNP RESIDUES 1093-1411 / Mutation: YES
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: Q9UM73, 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


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


Mass: 18.015 Da / Num. of mol.: 227 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsRESIDUES 1093-1411, CONTAINING MUTATION L1198F, OF HUMAN ANAPLASTIC LYMPHOMA KINASE PLUS AN ...RESIDUES 1093-1411, CONTAINING MUTATION L1198F, OF HUMAN ANAPLASTIC LYMPHOMA KINASE PLUS AN ENGINEERED N-TERMINAL HIS-TAG.

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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: 2.1 Å3/Da / Density % sol: 0.41 % / Description: NONE
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 8
Details: HANGING DROP VAPOR DIFFUSION AT 13 DEGREES C. 2 MICROLITERS OF PURIFIED PROTEIN SOLUTION (11-15 MG/ML) CONTAINING INHIBITOR COMPOUND AT A 2X STOICHIOMETRY OF INHIBITOR TO PROTEIN WERE ...Details: HANGING DROP VAPOR DIFFUSION AT 13 DEGREES C. 2 MICROLITERS OF PURIFIED PROTEIN SOLUTION (11-15 MG/ML) CONTAINING INHIBITOR COMPOUND AT A 2X STOICHIOMETRY OF INHIBITOR TO PROTEIN WERE COMBINED WITH 2 MICROLITERS OF SOLUTIONS CONTAINING: 0.2 M LITHIUM SULFATE, 17-21% PEG3350 AND 0.1M TRIS PH 7.6-8.5.

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Data collection

DiffractionMean temperature: 87 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 0.9795
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 24, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.73→104.7 Å / Num. obs: 29735 / % possible obs: 89.7 % / Observed criterion σ(I): 1 / Redundancy: 5.7 % / Biso Wilson estimate: 24.6 Å2 / Rmerge(I) obs: 0.04 / Net I/σ(I): 23.7
Reflection shellResolution: 1.73→1.85 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.33 / Mean I/σ(I) obs: 2.8 / % possible all: 58.2

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Processing

Software
NameVersionClassification
CNX2005refinement
autoPROCdata reduction
Aimlessdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2XP2

2xp2


Resolution: 1.73→52.35 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 1159509.72 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.206 866 2.9 %RANDOM
Rwork0.2 ---
obs0.201 29598 89.5 %-
all-29598 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 49.6427 Å2 / ksol: 0.377568 e/Å3
Displacement parametersBiso mean: 30.6 Å2
Baniso -1Baniso -2Baniso -3
1--0.4 Å20 Å20 Å2
2---4.56 Å20 Å2
3---4.96 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.23 Å0.21 Å
Luzzati d res low-5 Å
Luzzati sigma a0.19 Å0.18 Å
Refinement stepCycle: LAST / Resolution: 1.73→52.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2317 0 30 227 2574
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_d19.2
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_it1.51.5
X-RAY DIFFRACTIONc_mcangle_it2.422
X-RAY DIFFRACTIONc_scbond_it2.342
X-RAY DIFFRACTIONc_scangle_it3.562.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 1.73→1.84 Å / Rfactor Rfree error: 0.043 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.394 84 2.7 %
Rwork0.344 3001 -
obs--56.8 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAPROTEIN.TOP
X-RAY DIFFRACTION2DNA-RNA_REP.PARADNA-RNA.TOP
X-RAY DIFFRACTION3WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION4ION.PARAMION.TOP
X-RAY DIFFRACTION5VGH.PARAMVGH.TOP

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