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- PDB-7jys: hALK in complex with 3-(3-chlorophenyl)-5-methyl-1H-pyrazole -

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Basic information

Entry
Database: PDB / ID: 7jys
TitlehALK in complex with 3-(3-chlorophenyl)-5-methyl-1H-pyrazole
ComponentsALK tyrosine kinase receptor
KeywordsTRANSFERASE / ALK tyrosine kinase receptor / INHIBITOR / COMPLEX / KINASE / SBDD / 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 / response to stress / adult behavior / negative regulation of lipid catabolic process / neuron development / cell surface receptor protein tyrosine kinase signaling pathway / energy homeostasis / peptidyl-tyrosine autophosphorylation / transmembrane receptor protein tyrosine kinase activity / hippocampus development / receptor protein-tyrosine kinase / Signaling by ALK fusions and activated point mutants / heparin binding / regulation of cell population proliferation / positive regulation of NF-kappaB transcription factor activity / protein tyrosine kinase activity / regulation of apoptotic process / protein autophosphorylation / phosphorylation / 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 / Low-density lipoprotein (LDL) receptor class A repeat / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / 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 / Low-density lipoprotein (LDL) receptor class A repeat / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / 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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
3-(3-chlorophenyl)-5-methyl-1H-pyrazole / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.22 Å
AuthorsMcGrath, A.P. / Zou, H. / Lane, W. / Saikatendu, K.
CitationJournal: Acs Omega / Year: 2020
Title: Discovery of Novel and Highly Selective Cyclopropane ALK Inhibitors through a Fragment-Assisted, Structure-Based Drug Design.
Authors: Fujimori, I. / Wakabayashi, T. / Murakami, M. / Okabe, A. / Ishii, T. / McGrath, A. / Zou, H. / Saikatendu, K.S. / Imoto, H.
History
DepositionAug 31, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 20, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 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)36,3003
Polymers36,0451
Non-polymers2552
Water99155
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: homology
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area190 Å2
ΔGint3 kcal/mol
Surface area13250 Å2
Unit cell
Length a, b, c (Å)51.730, 56.887, 103.563
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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


Mass: 36045.371 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALK / Plasmid: pFastBacHTb / Cell (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Chemical ChemComp-VTD / 3-(3-chlorophenyl)-5-methyl-1H-pyrazole


Mass: 192.645 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H9ClN2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 55 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.11 Å3/Da / Density % sol: 41.81 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 8
Details: 25 mM Tris pH 8.0, 150 mM NaCl, 0.5 mM EDTA, 0.25 mM TCEP

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.976 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 5, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.22→29.51 Å / Num. obs: 15566 / % possible obs: 99.13 % / Redundancy: 6.1 % / Biso Wilson estimate: 43.31 Å2 / Rmerge(I) obs: 0.098 / Net I/σ(I): 16.16
Reflection shellResolution: 2.22→2.299 Å / Rmerge(I) obs: 0.897 / Mean I/σ(I) obs: 2.36 / Num. unique obs: 1458 / % possible all: 94.97

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Processing

Software
NameVersionClassification
PHENIX1.18.1_3865refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4z55

4z55


Resolution: 2.22→29.51 Å / SU ML: 0.2686 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.71
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2528 779 5.01 %
Rwork0.2141 14781 -
obs0.216 15560 99.19 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 55.83 Å2
Refinement stepCycle: LAST / Resolution: 2.22→29.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2201 0 17 55 2273
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032307
X-RAY DIFFRACTIONf_angle_d0.58523132
X-RAY DIFFRACTIONf_chiral_restr0.0414344
X-RAY DIFFRACTIONf_plane_restr0.0048406
X-RAY DIFFRACTIONf_dihedral_angle_d23.6173864
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.22-2.360.33681260.29822344X-RAY DIFFRACTION96
2.36-2.540.27151300.26842400X-RAY DIFFRACTION99.68
2.54-2.80.26711530.23572436X-RAY DIFFRACTION99.96
2.8-3.20.26111330.22132475X-RAY DIFFRACTION100
3.2-4.030.22651090.19642519X-RAY DIFFRACTION100
4.03-29.510.24491280.19722607X-RAY DIFFRACTION99.49

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