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- PDB-8arj: Anaplastic Lymphoma Kinase with a novel carboline inhibitor -

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Basic information

Entry
Database: PDB / ID: 8arj
TitleAnaplastic Lymphoma Kinase with a novel carboline inhibitor
ComponentsALK tyrosine kinase receptor
KeywordsANTITUMOR PROTEIN / inhibitor / ALK / kinase / antitumor
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 / 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-NRR / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.645 Å
AuthorsMologni, L. / Scapozza, L. / Gambacorti-Passerini, C. / Tardy, S. / Goekjian, P. / Robinson, C. / Brown, D.
Funding support Italy, European Union, 3items
OrganizationGrant numberCountry
Other governmentItalian Ministry of Research 3/13 Italy
Italian Association for Cancer ResearchIG-24828 Italy
European CommissionITN 675712 and 503467European Union
CitationJournal: Acs Omega / Year: 2022
Title: Discovery of Novel alpha-Carboline Inhibitors of the Anaplastic Lymphoma Kinase.
Authors: Mologni, L. / Tardy, S. / Zambon, A. / Orsato, A. / Bisson, W.H. / Ceccon, M. / Viltadi, M. / D'Attoma, J. / Pannilunghi, S. / Vece, V. / Bertho, J. / Goekjian, P. / Scapozza, L. / Gambacorti-Passerini, C.
History
DepositionAug 17, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 14, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: 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)36,4622
Polymers36,0221
Non-polymers4401
Water1,13563
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12920 Å2
Unit cell
Length a, b, c (Å)51.714, 56.593, 103.243
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: 36022.336 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Chemical ChemComp-NRR / 3-(dimethylamino)-1-[3-[4-(4-methylpiperazin-1-yl)phenyl]-9~{H}-pyrido[2,3-b]indol-6-yl]prop-2-en-1-one


Mass: 439.552 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H29N5O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 63 / 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: 41.34 %
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop
Details: 0.15 M ammonium sulphate, 9-10.5% monomethyl ether poly (ethylene glycol) (MW 5000), and 0.1 M MES buffer pH 5.3 - 5.6
PH range: 5.3 - 5.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9159 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 6, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9159 Å / Relative weight: 1
ReflectionResolution: 1.645→46.281 Å / Num. obs: 26023 / % possible obs: 94 % / Redundancy: 6.3 % / CC1/2: 0.999 / Rmerge(I) obs: 0.069 / Rpim(I) all: 0.03 / Rrim(I) all: 0.076 / Net I/σ(I): 12.7
Reflection shellResolution: 1.645→1.821 Å / Redundancy: 5.7 % / Rmerge(I) obs: 1.287 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 1302 / CC1/2: 0.35 / Rpim(I) all: 0.583 / Rrim(I) all: 1.416 / % possible all: 58.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0352refinement
autoPROCdata reduction
autoPROCdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4CLI

4cli


Resolution: 1.645→46.281 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.945 / WRfactor Rfree: 0.239 / WRfactor Rwork: 0.207 / SU B: 3.119 / SU ML: 0.097 / Average fsc free: 0.9566 / Average fsc work: 0.9659 / Cross valid method: FREE R-VALUE / ESU R: 0.14 / ESU R Free: 0.13
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2287 1349 5.184 %
Rwork0.1966 24674 -
all0.198 --
obs-26023 69.282 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 40.512 Å2
Baniso -1Baniso -2Baniso -3
1--0.102 Å2-0 Å20 Å2
2---0.302 Å2-0 Å2
3---0.404 Å2
Refinement stepCycle: LAST / Resolution: 1.645→46.281 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2119 0 33 63 2215
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0122210
X-RAY DIFFRACTIONr_bond_other_d0.0010.0162023
X-RAY DIFFRACTIONr_angle_refined_deg1.5361.6483000
X-RAY DIFFRACTIONr_angle_other_deg0.5251.5564713
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2975272
X-RAY DIFFRACTIONr_dihedral_angle_2_deg16.4518
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.11810360
X-RAY DIFFRACTIONr_dihedral_angle_6_deg16.2571090
X-RAY DIFFRACTIONr_chiral_restr0.0770.2331
X-RAY DIFFRACTIONr_chiral_restr_other0.0140.21
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022494
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02427
X-RAY DIFFRACTIONr_nbd_refined0.2180.2462
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1980.21883
X-RAY DIFFRACTIONr_nbtor_refined0.1790.21102
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0790.21158
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1510.268
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1920.29
X-RAY DIFFRACTIONr_nbd_other0.1850.233
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.0310.21
X-RAY DIFFRACTIONr_mcbond_it3.3124.2491100
X-RAY DIFFRACTIONr_mcbond_other3.314.251100
X-RAY DIFFRACTIONr_mcangle_it5.0866.331368
X-RAY DIFFRACTIONr_mcangle_other5.0866.3321369
X-RAY DIFFRACTIONr_scbond_it4.3694.4361110
X-RAY DIFFRACTIONr_scbond_other4.3674.4361111
X-RAY DIFFRACTIONr_scangle_it6.8196.4991632
X-RAY DIFFRACTIONr_scangle_other6.8176.5031633
X-RAY DIFFRACTIONr_lrange_it10.29278.0939426
X-RAY DIFFRACTIONr_lrange_other10.29478.1119403
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.645-1.6880.6520.361810.36927340.5630.8733.03580.358
1.688-1.7340.366110.3012470.30426660.8630.9269.67740.302
1.734-1.7850.325270.2974420.29926270.9420.93117.85310.296
1.785-1.8390.319500.2877680.28924960.9370.9432.77240.281
1.839-1.90.308690.2812360.28224440.9460.94453.39610.273
1.9-1.9660.301860.28915450.2923700.9370.94168.81860.268
1.966-2.040.315970.26417180.26722650.9260.95180.13240.248
2.04-2.1230.282900.26218970.26322190.9490.95289.54480.236
2.123-2.2180.242900.2219830.22121130.960.96698.1070.196
2.218-2.3250.2451010.20219240.20420270.9620.97299.90130.181
2.325-2.4510.231050.18518580.18719640.9660.97899.94910.169
2.451-2.5990.231900.18517240.18818140.9630.9781000.173
2.599-2.7780.2581040.17716180.18217220.9620.981000.17
2.778-30.236820.19515520.19716350.9660.97699.93880.192
3-3.2850.22930.18813890.1914860.9690.97999.73080.193
3.285-3.670.205890.18712900.18813820.9770.9899.78290.2
3.67-4.2330.22450.16511580.16712080.9720.98399.58610.191
4.233-5.1740.199580.1669880.16810490.9760.98299.7140.205
5.174-7.2720.21370.2257790.2248210.9720.97199.3910.281
7.272-46.2810.201230.2094770.2085080.9620.97198.42520.298

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