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- PDB-5kz0: Structure of Human Anaplastic Lymphoma Kinase in Complex With 2-[... -

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Basic information

Entry
Database: PDB / ID: 5kz0
TitleStructure of Human Anaplastic Lymphoma Kinase in Complex With 2-[(1R)-1-{[2-amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl]oxy}ethyl]-4-fluoro-N,N-dimethylbenzamide
ComponentsALK tyrosine kinase receptor
KeywordsTransferase/Transferase Inhibitor / kinase / inhibitor / Transferase-Transferase Inhibitor complex
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 / 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-6YL / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.3 Å
AuthorsMcTigue, M. / Deng, Y.L. / Liu, W. / Brooun, A.
CitationJournal: J. Med. Chem. / Year: 2014
Title: Discovery of (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 (PF-06463922), a ...Title: Discovery of (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 (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations.
Authors: Johnson, T.W. / Richardson, P.F. / Bailey, S. / Brooun, A. / Burke, B.J. / Collins, M.R. / Cui, J.J. / Deal, J.G. / Deng, Y.L. / Dinh, D. / Engstrom, L.D. / He, M. / Hoffman, J. / Hoffman, R. ...Authors: Johnson, T.W. / Richardson, P.F. / Bailey, S. / Brooun, A. / Burke, B.J. / Collins, M.R. / Cui, J.J. / Deal, J.G. / Deng, Y.L. / Dinh, D. / Engstrom, L.D. / He, M. / Hoffman, J. / Hoffman, R.L. / Huang, Q. / Kania, R.S. / Kath, J.C. / Lam, H. / Lam, J.L. / Le, P.T. / Lingardo, L. / Liu, W. / McTigue, M. / Palmer, C.L. / Sach, N.W. / Smeal, T. / Smith, G.L. / Stewart, A.E. / Timofeevski, S. / Zhu, H. / Zhu, J. / Zou, H.Y. / Edwards, M.P.
History
DepositionJul 22, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 17, 2016Provider: repository / Type: Initial release
Revision 1.1Aug 9, 2017Group: Data collection / Derived calculations / Category: diffrn_source / pdbx_struct_oper_list
Item: _diffrn_source.pdbx_synchrotron_site / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)37,3072
Polymers36,9091
Non-polymers3971
Water3,531196
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.740, 57.070, 104.580
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein ALK tyrosine kinase receptor / Anaplastic lymphoma kinase


Mass: 36909.355 Da / Num. of mol.: 1 / Fragment: UNP residues 1093-1411
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALK / Plasmid: PFASTBAC / Cell (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Chemical ChemComp-6YL / 2-[(1~{R})-1-[2-azanyl-5-(1,3-dimethylpyrazol-4-yl)pyridin-3-yl]oxyethyl]-4-fluoranyl-~{N},~{N}-dimethyl-benzamide


Mass: 397.446 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H24FN5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 196 / 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: 2.09 Å3/Da / Density % sol: 41.19 %
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop
Details: HANGING DROP VAPOR DIFFUSION AT 13 DEGREES C. EQUAL VOLUMES OF PURIFIED PROTEIN SOLUTION(APPROXIMATELY 13-15 MG/ML)CONTAINING 0.0011M INHIBITOR COMPOUND WERE COMBINED WITH A SOLUTION ...Details: HANGING DROP VAPOR DIFFUSION AT 13 DEGREES C. EQUAL VOLUMES OF PURIFIED PROTEIN SOLUTION(APPROXIMATELY 13-15 MG/ML)CONTAINING 0.0011M INHIBITOR COMPOUND WERE COMBINED WITH A SOLUTION CONTAINING: 0.15M 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: Diamond / Beamline: I04 / Wavelength: 0.976 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Feb 3, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.16→500 Å / Num. obs: 20573 / % possible obs: 99.9 % / Redundancy: 6.5 % / Net I/σ(I): 7

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Processing

Software
NameVersionClassification
CNSrefinement
PDB_EXTRACT3.2data extraction
xia2data reduction
SCALAdata scaling
CNXphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4cli

4cli


Resolution: 2.3→51.74 Å / Cross valid method: FREE R-VALUE / σ(F): 1776
RfactorNum. reflection% reflection
Rfree0.2689 597 2.2 %
Rwork0.1805 --
obs-20573 77.7 %
Displacement parametersBiso max: 73.05 Å2 / Biso mean: 25.4667 Å2 / Biso min: 2.1 Å2
Baniso -1Baniso -2Baniso -3
1-0.001 Å20 Å20 Å2
2--0.02 Å20 Å2
3----0.02 Å2
Refinement stepCycle: final / Resolution: 2.3→51.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2303 0 225 0 2528
Biso mean--29.81 --
Num. residues----293
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_mcbond_it1.4251.5
X-RAY DIFFRACTIONc_scbond_it2.1752
X-RAY DIFFRACTIONc_mcangle_it2.4182
X-RAY DIFFRACTIONc_scangle_it3.2362.5
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1protein_rep.param
X-RAY DIFFRACTION2dna-rna_rep.param
X-RAY DIFFRACTION3water_rep.param
X-RAY DIFFRACTION4ion.param
X-RAY DIFFRACTION5unl.param

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