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- PDB-7jy4: hALK in complex with ((1S,2S)-1-(2,4-difluorophenyl)-2-(2-(3-meth... -

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Basic information

Entry
Database: PDB / ID: 7jy4
TitlehALK in complex with ((1S,2S)-1-(2,4-difluorophenyl)-2-(2-(3-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenoxy)cyclopropyl)methanamine
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 / adult behavior / Signaling by ALK / neuron development / negative regulation of lipid catabolic process / energy homeostasis / peptidyl-tyrosine autophosphorylation / transmembrane receptor protein tyrosine kinase activity / hippocampus development / cell surface receptor protein tyrosine kinase signaling pathway / Signaling by ALK fusions and activated point mutants / receptor protein-tyrosine kinase / heparin binding / positive regulation of NF-kappaB transcription factor activity / 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 / 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
Chem-W47 / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.42 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 28, 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)36,8923
Polymers36,0451
Non-polymers8472
Water66737
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: homology
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13850 Å2
Unit cell
Length a, b, c (Å)51.479, 56.747, 103.568
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab

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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 line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Chemical ChemComp-W47 / 1-{(1S,2S)-1-(2,4-difluorophenyl)-2-[2-(3-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenoxy]cyclopropyl}methanamine


Mass: 423.379 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H18F5N3O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 37 / 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: 2.1 Å3/Da / Density % sol: 41.38 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 18.25% PEG 3350, 2% Tacsimate pH 7.0, 0.09M Tris Cl, 0.01M Tris_base

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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: Feb 1, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.42→24.98 Å / Num. obs: 11973 / % possible obs: 98.41 % / Redundancy: 6.4 % / Biso Wilson estimate: 48.79 Å2 / Rmerge(I) obs: 0.099 / Net I/σ(I): 16.2
Reflection shellResolution: 2.42→2.506 Å / Rmerge(I) obs: 0.75 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 1105

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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: 2.42→24.98 Å / SU ML: 0.3031 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 30.8528
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.2554 575 4.8 %Random selection
Rwork0.2191 11398 --
obs0.221 11973 98.49 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 62.31 Å2
Refinement stepCycle: LAST / Resolution: 2.42→24.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2257 0 60 37 2354
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00222378
X-RAY DIFFRACTIONf_angle_d0.58853237
X-RAY DIFFRACTIONf_chiral_restr0.0411349
X-RAY DIFFRACTIONf_plane_restr0.0037429
X-RAY DIFFRACTIONf_dihedral_angle_d23.775872
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.42-2.660.34551450.2792672X-RAY DIFFRACTION94.72
2.66-3.040.31791280.25862853X-RAY DIFFRACTION99.27
3.04-3.830.26031370.22182879X-RAY DIFFRACTION99.93
3.83-24.980.22661650.19652994X-RAY DIFFRACTION99.91

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