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- PDB-5imx: Anaplastic lymphoma kinase (ALK) catalytic domain complexed with ... -

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Basic information

Entry
Database: PDB / ID: 5imx
TitleAnaplastic lymphoma kinase (ALK) catalytic domain complexed with novel inhibitor 3-sulfonylpyrazol-4-amino pyrimidine
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 / peptidyl-tyrosine autophosphorylation / energy homeostasis / cell surface receptor protein tyrosine kinase signaling pathway / transmembrane receptor protein tyrosine kinase activity / phosphorylation / 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 / 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. / 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-CZ4 / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.12 Å
AuthorsWang, C. / Zhang, P. / Dong, J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2016
Title: Design and synthesis of novel 3-sulfonylpyrazol-4-amino pyrimidines as potent anaplastic lymphoma kinase (ALK) inhibitors.
Authors: Zhang, P. / Dong, J. / Zhong, B. / Zhang, D. / Yuan, H. / Jin, C. / Xu, X. / Li, H. / Zhou, Y. / Liang, Z. / Ji, M. / Xu, T. / Song, G. / Zhang, L. / Chen, G. / Meng, X. / Sun, D. / Shih, J. ...Authors: Zhang, P. / Dong, J. / Zhong, B. / Zhang, D. / Yuan, H. / Jin, C. / Xu, X. / Li, H. / Zhou, Y. / Liang, Z. / Ji, M. / Xu, T. / Song, G. / Zhang, L. / Chen, G. / Meng, X. / Sun, D. / Shih, J. / Zhang, R. / Hou, G. / Wang, C. / Jin, Y. / Yang, Q.
History
DepositionMar 7, 2016Deposition site: RCSB / Processing site: PDBJ
Revision 1.0May 4, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 20, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_prerelease_seq / 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

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Assembly

Deposited unit
A: ALK tyrosine kinase receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,4862
Polymers36,9091
Non-polymers5761
Water54030
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12370 Å2
Unit cell
Length a, b, c (Å)51.698, 56.759, 104.556
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 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Chemical ChemComp-CZ4 / 5-chloro-N~2~-{5-methyl-4-(1-methylpiperidin-4-yl)-2-[(propan-2-yl)oxy]phenyl}-N~4~-{1-methyl-3-[(propan-2-yl)sulfonyl]-1H-pyrazol-4-yl}pyrimidine-2,4-diamine


Mass: 576.154 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H38ClN7O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 30 / 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: 2.08 Å3/Da / Density % sol: 40.81 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5 / Details: 18% PEG 3350, 0.1 M Tris-HCl, PH 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.979 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Sep 13, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.12→50 Å / Num. obs: 19144 / % possible obs: 88.8 % / Redundancy: 6.5 % / Net I/σ(I): 34.9
Reflection shellResolution: 2.12→2.15 Å / Redundancy: 6.6 % / Rmerge(I) obs: 0.515 / Mean I/σ(I) obs: 4.2 / % possible all: 100

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
REFMAC5.8.0049refinement
PDB_EXTRACT3.2data extraction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.12→46.34 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.917 / SU B: 5.303 / SU ML: 0.143 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.057 / ESU R Free: 0.047
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES
RfactorNum. reflection% reflectionSelection details
Rfree0.2593 816 5.1 %RANDOM
Rwork0.2105 ---
obs0.213 15084 87.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 134.88 Å2 / Biso mean: 48.517 Å2 / Biso min: 23.09 Å2
Baniso -1Baniso -2Baniso -3
1--17.28 Å2-0 Å2-0 Å2
2---20.43 Å2-0 Å2
3---37.71 Å2
Refinement stepCycle: final / Resolution: 2.12→46.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2066 0 39 30 2135
Biso mean--49.11 41.24 -
Num. residues----266
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0192157
X-RAY DIFFRACTIONr_bond_other_d0.0020.022056
X-RAY DIFFRACTIONr_angle_refined_deg1.931.9952933
X-RAY DIFFRACTIONr_angle_other_deg0.92134731
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.6275262
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.56623.84691
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.23415348
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.211514
X-RAY DIFFRACTIONr_chiral_restr0.1020.2325
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0212401
X-RAY DIFFRACTIONr_gen_planes_other0.0080.02480
X-RAY DIFFRACTIONr_mcbond_it4.0854.7811060
X-RAY DIFFRACTIONr_mcbond_other4.0784.7781059
X-RAY DIFFRACTIONr_mcangle_it5.9187.1321318
LS refinement shellResolution: 2.12→2.175 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.229 65 -
Rwork0.215 1241 -
all-1306 -
obs--99.39 %

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