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- PDB-5a9u: Structure of C1156Y Mutant Human Anaplastic Lymphoma Kinase in Co... -

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Basic information

Entry
Database: PDB / ID: 5a9u
TitleStructure of C1156Y Mutant Human Anaplastic Lymphoma Kinase in Complex with PF-06463922 ((10R)-7-amino-12-fluoro-2,10,16-trimethyl- 15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecine-3-carbonitrile).
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 / 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
Chem-5P8 / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsMcTigue, M. / Deng, Y.-L. / 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 22, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 8, 2016Provider: repository / Type: Initial release
Revision 1.1Oct 12, 2016Group: Atomic model / Derived calculations / Non-polymer description
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 1.3Jan 10, 2024Group: 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: ALK TYROSINE KINASE RECEPTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,3762
Polymers36,9691
Non-polymers4061
Water3,567198
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.754, 57.587, 104.887
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: 36969.387 Da / Num. of mol.: 1 / Fragment: TYROSINE KINASE DOMAIN, RESIDUES 1093-1411 / Mutation: YES
Source method: isolated from a genetically manipulated source
Details: NONPHOSPHORYLATED / Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Chemical ChemComp-5P8 / (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile


Mass: 406.413 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H19FN6O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 198 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsRESIDUES 1093-1411 OF HUMAN ANAPLASTIC LYMPHOMA KINASE PLUS AN ENGINEERED N-TERMINAL HIS-TAG. ...RESIDUES 1093-1411 OF HUMAN ANAPLASTIC LYMPHOMA KINASE PLUS AN ENGINEERED N-TERMINAL HIS-TAG. RESIDUE CYS 1156 IS MUTATED TO TYR.

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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: 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: CLSI / Beamline: 08ID-1 / Wavelength: 0.9795
DetectorType: MARRESEARCH RAYONIX 300 / Detector: CCD / Date: May 18, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.59→50 Å / Num. obs: 42336 / % possible obs: 99.8 % / Observed criterion σ(I): 1 / Redundancy: 5.9 % / Biso Wilson estimate: 26.8 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 43
Reflection shellResolution: 1.59→1.65 Å / Redundancy: 5.6 % / Rmerge(I) obs: 0.92 / Mean I/σ(I) obs: 2 / % possible all: 99.9

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Processing

Software
NameVersionClassification
CNX2005refinement
HKL-2000data reduction
SCALAdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4CLJ

4clj


Resolution: 1.6→38.64 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 1121081.14 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.258 1253 3 %RANDOM
Rwork0.215 ---
obs0.216 41674 99.8 %-
all-41674 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 51.5425 Å2 / ksol: 0.386746 e/Å3
Displacement parametersBiso mean: 34.2 Å2
Baniso -1Baniso -2Baniso -3
1--2.42 Å20 Å20 Å2
2---5.97 Å20 Å2
3---8.39 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.24 Å0.2 Å
Luzzati d res low-5 Å
Luzzati sigma a0.18 Å0.19 Å
Refinement stepCycle: LAST / Resolution: 1.6→38.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2312 0 30 198 2540
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_d18.9
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.68
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.351.5
X-RAY DIFFRACTIONc_mcangle_it2.222
X-RAY DIFFRACTIONc_scbond_it2.092
X-RAY DIFFRACTIONc_scangle_it3.172.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 1.6→1.7 Å / Rfactor Rfree error: 0.023 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.322 194 2.8 %
Rwork0.289 6645 -
obs--100 %
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 DIFFRACTION5UNL.PARAMUNL.TOP

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