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- PDB-7r7r: Structure of Human Anaplastic Lymphoma Kinase Domain in complex w... -

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Basic information

Entry
Database: PDB / ID: 7r7r
TitleStructure of Human Anaplastic Lymphoma Kinase Domain in complex with ((2~{R})-2-[5-[6-amino-5-[(1~{R})-1-[5-fluoro-2-(triazol-2-yl)phenyl]ethoxy]-3-pyridyl]-4-methyl-thiazol-2-yl]propane-1,2-diol)
ComponentsALK tyrosine kinase receptor
KeywordsTRANSFERASE / kinase
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 / phosphorylation / positive regulation of dendrite development / regulation of neuron differentiation / peptidyl-tyrosine autophosphorylation / Signaling by ALK / adult behavior / response to stress / neuron development / negative regulation of lipid catabolic process / energy homeostasis / transmembrane receptor protein tyrosine kinase activity / cell surface receptor protein tyrosine kinase signaling pathway / hippocampus development / positive regulation of NF-kappaB transcription factor activity / receptor protein-tyrosine kinase / Signaling by ALK fusions and activated point mutants / heparin binding / regulation of cell population proliferation / protein autophosphorylation / protein tyrosine kinase activity / regulation of apoptotic process / 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 / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Low-density lipoprotein (LDL) receptor class A repeat / 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 / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Low-density lipoprotein (LDL) receptor class A repeat / 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-AWJ / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.935 Å
AuthorsMcTigue, M.
CitationJournal: Nat Cancer / Year: 2022
Title: Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer.
Authors: Shiba-Ishii, A. / Johnson, T.W. / Dagogo-Jack, I. / Mino-Kenudson, M. / Johnson, T.R. / Wei, P. / Weinrich, S.L. / McTigue, M.A. / Walcott, M.A. / Nguyen-Phuong, L. / Dionne, K. / Acker, A. ...Authors: Shiba-Ishii, A. / Johnson, T.W. / Dagogo-Jack, I. / Mino-Kenudson, M. / Johnson, T.R. / Wei, P. / Weinrich, S.L. / McTigue, M.A. / Walcott, M.A. / Nguyen-Phuong, L. / Dionne, K. / Acker, A. / Kiedrowski, L.A. / Do, A. / Peterson, J.L. / Barth, J.L. / Yeap, B.Y. / Gainor, J.F. / Lin, J.J. / Yoda, S. / Hata, A.N.
History
DepositionJun 25, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 29, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 10, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)37,3822
Polymers36,9091
Non-polymers4731
Water3,909217
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.496, 57.408, 104.9
Angle α, β, γ (deg.)90, 90, 90
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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALK / Plasmid: FASTBAC / Cell (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Chemical ChemComp-AWJ / (2R)-2-[5-(6-amino-5-{(1R)-1-[2-(1,3-dihydro-2H-1,2,3-triazol-2-yl)-5-fluorophenyl]ethoxy}pyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]propane-1,2-diol


Mass: 472.536 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H25FN6O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 217 / 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: 41.44 %
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop
Details: HANGING DROP VAPOR DIFFUSION AT 13 DEGREES C. EQUAL VOLUMES OF PURIFIED PROTEIN SOLUTION(APPROXIMATELY 13-15 MG/ML)CONTAINING 0.0011M INHIBITOR COMPOUND WERE COMBINED WITH A SOLUTION ...Details: HANGING DROP VAPOR DIFFUSION AT 13 DEGREES C. EQUAL VOLUMES OF PURIFIED PROTEIN SOLUTION(APPROXIMATELY 13-15 MG/ML)CONTAINING 0.0011M INHIBITOR COMPOUND WERE COMBINED WITH A SOLUTION CONTAINING: 0.15M AMMONIUM SULFATE, 9-10.5% MONOMETHYLETHER PEG5K AND 0.1M MES IN THE PH RANGE 5.3-6.5

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Data collection

DiffractionMean temperature: 95 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 4, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.93→57.41 Å / Num. obs: 23963 / % possible obs: 100 % / Redundancy: 6.5 % / Rmerge(I) obs: 0.06 / Rpim(I) all: 0.027 / Net I/σ(I): 21.8
Reflection shellResolution: 1.93→2.04 Å / Rmerge(I) obs: 0.471 / Num. unique obs: 3444 / Rpim(I) all: 0.219

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
SCALAdata scaling
CNSphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 2xp2

2xp2


Resolution: 1.935→52.45 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.918 / SU R Cruickshank DPI: 0.157 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.171 / SU Rfree Blow DPI: 0.148 / SU Rfree Cruickshank DPI: 0.142
RfactorNum. reflection% reflectionSelection details
Rfree0.2273 1223 -RANDOM
Rwork0.1911 ---
obs0.1929 23908 100 %-
Displacement parametersBiso mean: 28.58 Å2
Baniso -1Baniso -2Baniso -3
1-2.602 Å20 Å20 Å2
2--0.6533 Å20 Å2
3----3.2553 Å2
Refine analyzeLuzzati coordinate error obs: 0.23 Å
Refinement stepCycle: LAST / Resolution: 1.935→52.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2276 0 33 217 2526
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082367HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.943216HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d795SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes405HARMONIC5
X-RAY DIFFRACTIONt_it2367HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion304SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2255SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.23
X-RAY DIFFRACTIONt_other_torsion16.29
LS refinement shellResolution: 1.935→1.935 Å
RfactorNum. reflection% reflection
Rfree0.3091 23 -
Rwork0.2118 --
obs0.2159 479 100 %

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