[English] 日本語
Yorodumi
- PDB-8arj: Anaplastic Lymphoma Kinase with a novel carboline inhibitor -

+
Open data


ID or keywords:

Loading...

-
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 / negative regulation of lipid catabolic process / neuron development / phosphorylation / peptidyl-tyrosine autophosphorylation / energy homeostasis / cell surface receptor protein tyrosine kinase signaling pathway / transmembrane receptor protein tyrosine kinase activity / hippocampus development / receptor protein-tyrosine kinase / Signaling by ALK fusions and activated point mutants / positive regulation of NF-kappaB transcription factor activity / heparin binding / 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. / Concanavalin A-like lectin/glucanase domain superfamily / Tyrosine-protein kinase, active site / 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

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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

-
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

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
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

-
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

-
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

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more