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- PDB-2yfx: Structure of L1196M Mutant Anaplastic Lymphoma Kinase in Complex ... -

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Basic information

Entry
Database: PDB / ID: 2yfx
TitleStructure of L1196M Mutant Anaplastic Lymphoma Kinase in Complex with Crizotinib
ComponentsTYROSINE-PROTEIN KINASE RECEPTOR
KeywordsTRANSFERASE / NUCLEOTIDE-BINDING / RECEPTOR
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 / positive regulation of dendrite development / regulation of neuron differentiation / Signaling by ALK / adult behavior / neuron development / negative regulation of lipid catabolic process / phosphorylation / peptidyl-tyrosine autophosphorylation / cell surface receptor protein tyrosine kinase signaling pathway / energy homeostasis / transmembrane receptor protein tyrosine kinase activity / hippocampus development / receptor protein-tyrosine kinase / Signaling by ALK fusions and activated point mutants / 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 / signal transduction / protein-containing complex / extracellular exosome / ATP binding / identical protein binding / membrane / 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. / : ...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 / 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 / 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: 1.7 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
DepositionApr 8, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 4, 2011Provider: repository / Type: Initial release
Revision 1.1Mar 19, 2014Group: Database references / Derived calculations ...Database references / Derived calculations / Other / Version format compliance
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 ...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)37,3782
Polymers36,9271
Non-polymers4501
Water4,270237
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.721, 57.174, 105.253
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: 36927.391 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 105-423 / Mutation: YES
Source method: isolated from a genetically manipulated source
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


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


Mass: 18.015 Da / Num. of mol.: 237 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, LEU 208 TO MET

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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: 44.6 % / Description: NONE
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: HANGING DROP VAPOR DIFFUSION AT 13 DEGREES C. EQUAL VOLUMES OF PURIFIED PROTEIN SOLUTION (APPROXIMATELY 7 MG/ML)CONTAINING 0.8 MM CRIZOTINIB WERE COMBINED WITH A SOLUTION CONTAINING: 0.15 M ...Details: HANGING DROP VAPOR DIFFUSION AT 13 DEGREES C. EQUAL VOLUMES OF PURIFIED PROTEIN SOLUTION (APPROXIMATELY 7 MG/ML)CONTAINING 0.8 MM CRIZOTINIB WERE COMBINED WITH A SOLUTION CONTAINING: 0.15 M AMMONIUM SULFATE, 10% MONOMETHYLETHER PEG5K AND 0.1M MES PH 5.6.

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Data collection

DiffractionMean temperature: 98 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 12, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.57→105.25 Å / Num. obs: 43152 / % possible obs: 98.2 % / Observed criterion σ(I): 1 / Redundancy: 6.2 % / Biso Wilson estimate: 23.3 Å2 / Rmerge(I) obs: 0.05 / Net I/σ(I): 18.3
Reflection shellResolution: 1.57→1.66 Å / Redundancy: 2.2 % / Rmerge(I) obs: 0.34 / Mean I/σ(I) obs: 2 / % possible all: 91.5

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Processing

Software
NameVersionClassification
CNS2005refinement
XDSdata reduction
SCALAdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2XP2

2xp2


Resolution: 1.7→36.04 Å / Rfactor Rfree error: 0.006 / Data cutoff high absF: 1136270.83 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.234 1744 5 %RANDOM
Rwork0.208 ---
obs0.208 34791 99.1 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 50.7759 Å2 / ksol: 0.394385 e/Å3
Displacement parametersBiso mean: 28.2 Å2
Baniso -1Baniso -2Baniso -3
1--0.8 Å20 Å20 Å2
2---3.78 Å20 Å2
3---4.57 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.23 Å0.19 Å
Luzzati d res low-5 Å
Luzzati sigma a0.14 Å0.11 Å
Refinement stepCycle: LAST / Resolution: 1.7→36.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2300 0 30 237 2567
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_d0.67
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.381.5
X-RAY DIFFRACTIONc_mcangle_it2.212
X-RAY DIFFRACTIONc_scbond_it2.382
X-RAY DIFFRACTIONc_scangle_it3.582.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 1.7→1.81 Å / Rfactor Rfree error: 0.015 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.266 321 5.6 %
Rwork0.236 5425 -
obs--99.9 %
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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