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- PDB-4z55: Anaplastic lymphoma kinase catalytic domain complexed with pyrazo... -

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Basic information

Entry
Database: PDB / ID: 4z55
TitleAnaplastic lymphoma kinase catalytic domain complexed with pyrazolopyrimidine derivative of LDK378
ComponentsALK tyrosine kinase receptor
KeywordsTransferase/Transferase Inhibitor / catalytic domain / transferase / 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 / adult behavior / Signaling by ALK / neuron development / negative regulation of lipid catabolic process / energy homeostasis / peptidyl-tyrosine autophosphorylation / cell surface receptor protein tyrosine kinase signaling pathway / transmembrane receptor protein tyrosine kinase activity / hippocampus development / receptor protein-tyrosine kinase / Signaling by ALK fusions and activated point mutants / positive regulation of NF-kappaB transcription factor activity / heparin binding / regulation of cell population proliferation / regulation of apoptotic process / protein tyrosine kinase activity / protein autophosphorylation / receptor complex / phosphorylation / 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. / Tyrosine-protein kinase, catalytic domain ...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. / Concanavalin A-like lectin/glucanase domain superfamily / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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-4LO / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.55 Å
AuthorsLee, C.C. / Spraggon, G.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2016
Title: Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors.
Authors: Michellys, P.Y. / Chen, B. / Jiang, T. / Jin, Y. / Lu, W. / Marsilje, T.H. / Pei, W. / Uno, T. / Zhu, X. / Wu, B. / Nguyen, T.N. / Bursulaya, B. / Lee, C. / Li, N. / Kim, S. / Tuntland, T. / ...Authors: Michellys, P.Y. / Chen, B. / Jiang, T. / Jin, Y. / Lu, W. / Marsilje, T.H. / Pei, W. / Uno, T. / Zhu, X. / Wu, B. / Nguyen, T.N. / Bursulaya, B. / Lee, C. / Li, N. / Kim, S. / Tuntland, T. / Liu, B. / Sun, F. / Steffy, A. / Hood, T.
History
DepositionApr 2, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 3, 2016Provider: repository / Type: Initial release
Revision 1.1Feb 10, 2016Group: Database references
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: ALK tyrosine kinase receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,0004
Polymers38,2381
Non-polymers7623
Water3,549197
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area510 Å2
ΔGint0 kcal/mol
Surface area13230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.560, 57.520, 105.420
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: 38237.871 Da / Num. of mol.: 1 / Fragment: UNP residues 1072-1410 / Mutation: S1281G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-4LO / N~6~-[5-methyl-4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]-N~4~-[2-(propan-2-ylsulfonyl)phenyl]-2H-pyrazolo[3,4-d]pyrimidine-4,6-diamine


Mass: 577.741 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H39N7O3S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 197 / 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: 2.04 Å3/Da / Density % sol: 39.83 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.6 / Details: citric acid, bis-tris propane, PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9765 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 12, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9765 Å / Relative weight: 1
ReflectionResolution: 1.55→50 Å / Num. obs: 45757 / % possible obs: 98 % / Redundancy: 4.2 % / Biso Wilson estimate: 15.38 Å2 / Rmerge(I) obs: 0.063 / Rpim(I) all: 0.035 / Rrim(I) all: 0.068 / Χ2: 0.917 / Net I/av σ(I): 16.418 / Net I/σ(I): 7.5 / Num. measured all: 193008
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Num. unique allCC1/2Χ2% possible allRpim(I) allRmerge(I) obsRrim(I) all
1.55-1.582.720680.180.68989.9
1.58-1.613.122030.1590.75896.2
1.61-1.643.622690.2630.74898.9
1.64-1.67422970.3990.75299.70.976
1.67-1.714.323010.4230.81599.90.785
1.71-1.754.422960.5040.84599.90.62
1.75-1.794.423090.6450.85899.80.4920.97
1.79-1.844.422960.7380.8851000.40.7850.887
1.84-1.894.423120.8210.95599.70.3090.6130.691
1.89-1.954.422910.8930.96899.60.2210.4350.491
1.95-2.024.422870.9430.97499.40.1550.3080.346
2.02-2.14.423240.9611.02899.40.1160.2310.261
2.1-2.24.423060.9741.01599.10.090.1780.201
2.2-2.324.523040.9851.00498.90.0680.1350.152
2.32-2.464.522940.9891.00398.20.0550.1080.122
2.46-2.654.523120.9890.96998.50.0480.0940.106
2.65-2.924.522960.9891.00797.70.0420.0820.093
2.92-3.344.423040.9931.02497.30.0310.060.068
3.34-4.214.423090.9980.95495.60.020.0410.046
4.21-504.523790.9990.83293.40.0130.0260.029

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Processing

Software
NameVersionClassification
HKL-2000data collection
HKL-2000data scaling
BUSTER-TNTBUSTER 2.11.5refinement
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
BUSTERphasing
RefinementResolution: 1.55→46.32 Å / Cor.coef. Fo:Fc: 0.9451 / Cor.coef. Fo:Fc free: 0.9279 / SU R Cruickshank DPI: 0.108 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.113 / SU Rfree Blow DPI: 0.104 / SU Rfree Cruickshank DPI: 0.101
RfactorNum. reflection% reflectionSelection details
Rfree0.2081 1602 4.92 %RANDOM
Rwork0.1843 ---
obs0.1855 32543 70.3 %-
Displacement parametersBiso max: 98.6 Å2 / Biso mean: 20.63 Å2 / Biso min: 3.16 Å2
Baniso -1Baniso -2Baniso -3
1--0.0427 Å20 Å20 Å2
2--1.1681 Å20 Å2
3----1.1253 Å2
Refine analyzeLuzzati coordinate error obs: 0.191 Å
Refinement stepCycle: final / Resolution: 1.55→46.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2280 0 53 197 2530
Biso mean--20.51 30.92 -
Num. residues----294
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d831SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes53HARMONIC2
X-RAY DIFFRACTIONt_gen_planes357HARMONIC5
X-RAY DIFFRACTIONt_it2430HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion311SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies8HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3018SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2430HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3308HARMONIC20.99
X-RAY DIFFRACTIONt_omega_torsion3.13
X-RAY DIFFRACTIONt_other_torsion15.08
LS refinement shellResolution: 1.55→1.6 Å / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.2132 1 3.45 %
Rwork0.2016 28 -
all0.202 29 -
obs--70.3 %

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