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- PDB-6edl: hALK in complex with compound 1 (S)-N-(1-(2,4-difluorophenyl)ethy... -

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Basic information

Entry
Database: PDB / ID: 6edl
TitlehALK in complex with compound 1 (S)-N-(1-(2,4-difluorophenyl)ethyl)-3-(3-methyl-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-amine
ComponentsALK tyrosine kinase receptor
KeywordsTRANSFERASE/INHIBITOR / 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 / 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-J4M / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.799 Å
AuthorsLane, W. / Saikatendu, K.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Discovery of Potent, Selective, and Brain-Penetrant 1 H-Pyrazol-5-yl-1 H-pyrrolo[2,3- b]pyridines as Anaplastic Lymphoma Kinase (ALK) Inhibitors.
Authors: Fushimi, M. / Fujimori, I. / Wakabayashi, T. / Hasui, T. / Kawakita, Y. / Imamura, K. / Kato, T. / Murakami, M. / Ishii, T. / Kikko, Y. / Kasahara, M. / Nakatani, A. / Hiura, Y. / Miyamoto, ...Authors: Fushimi, M. / Fujimori, I. / Wakabayashi, T. / Hasui, T. / Kawakita, Y. / Imamura, K. / Kato, T. / Murakami, M. / Ishii, T. / Kikko, Y. / Kasahara, M. / Nakatani, A. / Hiura, Y. / Miyamoto, M. / Saikatendu, K. / Zou, H. / Lane, S.W. / Lawson, J.D. / Imoto, H.
History
DepositionAug 9, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2019Provider: repository / Type: Initial release
Revision 1.1May 8, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2May 15, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.3Jun 5, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.4Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)36,4002
Polymers36,0451
Non-polymers3541
Water25214
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.571, 57.409, 103.410
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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 / Production host: unidentified baculovirus
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Chemical ChemComp-J4M / N-[(1S)-1-(2,4-difluorophenyl)ethyl]-3-(5-methyl-1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-6-amine


Mass: 354.357 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H16F2N6 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 14 / 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: 2.12 Å3/Da / Density % sol: 42.07 %
Crystal growTemperature: 278 K / Method: vapor diffusion
Details: 20 mM Tris pH 8.0, 150 mM NaCl, 0.5 mM EDTA, 1 mM Benzamidine and 0.25 mM TCEP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X6A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 270 / Detector: CCD / Date: Jan 28, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→38.42 Å / Num. obs: 7935 / % possible obs: 99.21 % / Redundancy: 6 % / Biso Wilson estimate: 57.87 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.162 / Rpim(I) all: 0.071 / Net I/σ(I): 15.1
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.872 / Mean I/σ(I) obs: 2.72 / Num. unique obs: 731 / CC1/2: 0.66 / Rpim(I) all: 0.422 / % possible all: 93.13

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Processing

Software
NameVersionClassification
PHENIX(1.13_2998: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.799→38.42 Å / SU ML: 0.31 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 31.52 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2824 635 8 %RANDOM
Rwork0.227 ---
obs0.2314 7933 99.1 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.799→38.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2172 0 26 14 2212
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072269
X-RAY DIFFRACTIONf_angle_d1.2983092
X-RAY DIFFRACTIONf_dihedral_angle_d4.11891
X-RAY DIFFRACTIONf_chiral_restr0.073347
X-RAY DIFFRACTIONf_plane_restr0.006400
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.799-3.0150.34971200.29691382X-RAY DIFFRACTION96
3.015-3.31830.29471250.27071432X-RAY DIFFRACTION100
3.3183-3.79810.25961270.22031455X-RAY DIFFRACTION100
3.7981-4.78380.27741290.20111480X-RAY DIFFRACTION100
4.7838-38.42330.27841340.21961549X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 13.8264 Å / Origin y: -9.8619 Å / Origin z: -16.9649 Å
111213212223313233
T0.2426 Å2-0.0274 Å2-0.0129 Å2-0.265 Å2-0.0697 Å2--0.2896 Å2
L1.7843 °2-0.604 °20.1111 °2-2.2303 °2-0.4706 °2--2.0346 °2
S-0.0022 Å °0.0119 Å °-0.061 Å °-0.0096 Å °0.1211 Å °-0.1178 Å °0.129 Å °-0.0643 Å °0.0002 Å °
Refinement TLS groupSelection details: all

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