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- PDB-4ccb: Structure of the Human Anaplastic Lymphoma Kinase in Complex with... -

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Basic information

Entry
Database: PDB / ID: 4ccb
TitleStructure of the Human Anaplastic Lymphoma Kinase in Complex with 3-((R)-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)-5-(5-methyl-1H- pyrazol-4-yl)pyridin-2-amine
ComponentsALK TYROSINE KINASE RECEPTOR
KeywordsTRANSFERASE / RECEPTOR TYROSINE KINASE / ANAPLASTIC LYMPHOMA KINASE / INHIBITOR
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-OFG / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.03 Å
AuthorsMcTigue, M. / Deng, Y. / Liu, W. / Brooun, A. / Stewart, A.
CitationJournal: J.Med.Chem. / Year: 2014
Title: The Design of Potent and Selective Inhibitors to Overcome Clinical Alk 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. / Cui, J.J. / Dack, K.N. / Deal, J.G. / Deng, Y. / Dinh, D.M. / Engstrom, L.D. / ...Authors: Huang, Q. / Johnson, T.W. / Bailey, S. / Brooun, A. / Bunker, K.D. / Burke, B.J. / Collins, M.R. / Cook, A. / Cui, J.J. / Dack, K.N. / Deal, J.G. / Deng, Y. / Dinh, D.M. / Engstrom, L.D. / He, M. / Hoffman, J. / Hoffman, R.L. / Shen, H. / Johnson, P. / Kania, R.S. / Lam, H. / Lam, J.L. / Le, P. / Li, Q. / Lingardo, L. / Liu, W. / West Lu, M. / Mctigue, M.A. / Palmer, C.L. / Richardson, P.F. / Sach, N.W. / Smeal, T. / Smith, G.L. / Stewart, A.E. / Timofeevski, S.L. / Tsaparikos, K. / Wang, H. / Zhu, H. / Zhu, J. / Zou, H.Y. / Edwards, M.
History
DepositionOct 21, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 29, 2014Provider: repository / Type: Initial release
Revision 1.1Mar 12, 2014Group: Database references
Revision 1.2Apr 4, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_beamline
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 1.4Dec 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: ALK TYROSINE KINASE RECEPTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,2892
Polymers36,9091
Non-polymers3791
Water3,207178
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.545, 57.335, 104.972
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 / ANAPLASTIC LYMPHOMA KINASE


Mass: 36909.355 Da / Num. of mol.: 1 / Fragment: TYROSINE KINASE DOMAIN, RESIDUES 1093-1411
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-OFG / 3-[(1R)-1-[5-fluoranyl-2-(1,2,3-triazol-2-yl)phenyl]ethoxy]-5-(3-methyl-1H-pyrazol-4-yl)pyridin-2-amine


Mass: 379.391 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H18FN7O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 178 / 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: 2.1 Å3/Da / Density % sol: 41.4 % / Description: NONE
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: CRYSTALLIZATION CONDITIONS: HANGING DROP VAPOR DIFFUSION AT 13 DEGREES C. EQUAL VOLUMES OF PURIFIED PROTEIN SOLUTION (APPROXIMATELY 13-15 MG/ML)CONTAINING 0.001 M INHIBITOR COMPOUND WERE ...Details: CRYSTALLIZATION CONDITIONS: HANGING DROP VAPOR DIFFUSION AT 13 DEGREES C. EQUAL VOLUMES OF PURIFIED PROTEIN SOLUTION (APPROXIMATELY 13-15 MG/ML)CONTAINING 0.001 M INHIBITOR COMPOUND WERE COMBINED WITH A SOLUTION CONTAINING: 0.15 M AMMONIUM SULFATE, 9-10.5% MONOMETHYLETHER PEG5K AND 0.1M MES IN THE PH RANGE 5.3-6.5.

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Data collection

DiffractionMean temperature: 87 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Type: ALS / Wavelength: 0.977
DetectorType: ADSC CCD / Detector: CCD / Date: Jan 29, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.977 Å / Relative weight: 1
ReflectionResolution: 1.88→50 Å / Num. obs: 26123 / % possible obs: 99.7 % / Observed criterion σ(I): 1 / Redundancy: 6.8 % / Biso Wilson estimate: 16.4 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 3.4
Reflection shellResolution: 1.88→1.91 Å / Redundancy: 5.2 % / Rmerge(I) obs: 0.6 / Mean I/σ(I) obs: 3.1 / % possible all: 95.6

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Processing

Software
NameVersionClassification
CNX2005refinement
HKL-2000data reduction
SCALEPACKdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2XP2

2xp2


Resolution: 2.03→46.27 Å / Rfactor Rfree error: 0.01 / Data cutoff high absF: 69529.02 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.235 565 2.8 %RANDOM
Rwork0.201 ---
obs0.202 20223 97.4 %-
all-20740 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 49.7444 Å2 / ksol: 0.374721 e/Å3
Displacement parametersBiso mean: 30 Å2
Baniso -1Baniso -2Baniso -3
1--1.91 Å20 Å20 Å2
2---4.23 Å20 Å2
3---6.14 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.25 Å0.21 Å
Luzzati d res low-5 Å
Luzzati sigma a0.19 Å0.11 Å
Refinement stepCycle: LAST / Resolution: 2.03→46.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2276 0 28 178 2482
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_d19.3
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.66
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.531.5
X-RAY DIFFRACTIONc_mcangle_it2.422
X-RAY DIFFRACTIONc_scbond_it2.452
X-RAY DIFFRACTIONc_scangle_it3.632.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 2.03→2.16 Å / Rfactor Rfree error: 0.027 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.275 102 3.2 %
Rwork0.218 3073 -
obs--93.8 %
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 DIFFRACTION5OFG.PARAMOFG.TOP

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