[English] 日本語
Yorodumi
- EMDB-24095: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: EMDB / ID: EMD-24095
TitleAnaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 648-1025 in complex with AUG-alpha
Map dataAnaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 in complex with AUG-alpha
Sample
  • Complex: hetero-tetrameric complex of anaplastic lymphoma kinase (ALK) with Augmentor alpha
    • Protein or peptide: ALK tyrosine kinase receptor
    • Protein or peptide: ALK and LTK ligand 2
Function / homology
Function and homology information


positive regulation of ERK5 cascade / response to environmental enrichment / 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 / receptor signaling protein tyrosine kinase activator activity ...positive regulation of ERK5 cascade / response to environmental enrichment / 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 / receptor signaling protein tyrosine kinase activator activity / regulation of dopamine receptor signaling pathway / ALK mutants bind TKIs / swimming behavior / positive regulation of dendrite development / regulation of neuron differentiation / adult behavior / Signaling by ALK / transmembrane receptor protein tyrosine kinase activator activity / Signaling by ALK fusions and activated point mutants / neuron development / Nuclear events stimulated by ALK signaling in cancer / negative regulation of lipid catabolic process / energy homeostasis / peptidyl-tyrosine autophosphorylation / transmembrane receptor protein tyrosine kinase activity / cytokine activity / hippocampus development / positive regulation of neuron projection development / receptor tyrosine kinase binding / receptor protein-tyrosine kinase / cell surface receptor protein tyrosine kinase signaling pathway / 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 / positive regulation of ERK1 and ERK2 cascade / receptor complex / phosphorylation / signal transduction / protein-containing complex / extracellular space / extracellular exosome / extracellular region / ATP binding / identical protein binding / plasma membrane
Similarity search - Function
ALK and LTK ligand 1/2 / ALK and LTK ligand 1/2 / 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 ...ALK and LTK ligand 1/2 / ALK and LTK ligand 1/2 / 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 / Concanavalin A-like lectin/glucanase domain superfamily / Tyrosine protein kinases specific active-site signature. / 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
ALK and LTK ligand 2 / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.27 Å
AuthorsMyasnikov AG / Reshetnyak AV / Kalodimos CG
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM122462 United States
CitationJournal: Nature / Year: 2021
Title: Mechanism for the activation of the anaplastic lymphoma kinase receptor.
Authors: Andrey V Reshetnyak / Paolo Rossi / Alexander G Myasnikov / Munia Sowaileh / Jyotidarsini Mohanty / Amanda Nourse / Darcie J Miller / Irit Lax / Joseph Schlessinger / Charalampos G Kalodimos /
Abstract: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that regulates important functions in the central nervous system. The ALK gene is a hotspot for chromosomal translocation events ...Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that regulates important functions in the central nervous system. The ALK gene is a hotspot for chromosomal translocation events that result in several fusion proteins that cause a variety of human malignancies. Somatic and germline gain-of-function mutations in ALK were identified in paediatric neuroblastoma. ALK is composed of an extracellular region (ECR), a single transmembrane helix and an intracellular tyrosine kinase domain. ALK is activated by the binding of ALKAL1 and ALKAL2 ligands to its ECR, but the lack of structural information for the ALK-ECR or for ALKAL ligands has limited our understanding of ALK activation. Here we used cryo-electron microscopy, nuclear magnetic resonance and X-ray crystallography to determine the atomic details of human ALK dimerization and activation by ALKAL1 and ALKAL2. Our data reveal a mechanism of RTK activation that allows dimerization by either dimeric (ALKAL2) or monomeric (ALKAL1) ligands. This mechanism is underpinned by an unusual architecture of the receptor-ligand complex. The ALK-ECR undergoes a pronounced ligand-induced rearrangement and adopts an orientation parallel to the membrane surface. This orientation is further stabilized by an interaction between the ligand and the membrane. Our findings highlight the diversity in RTK oligomerization and activation mechanisms.
History
DepositionMay 24, 2021-
Header (metadata) releaseNov 24, 2021-
Map releaseNov 24, 2021-
UpdateDec 15, 2021-
Current statusDec 15, 2021Processing site: RCSB / Status: Released

-
Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.005
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.005
  • Imaged by UCSF Chimera
  • Download
  • Surface view with fitted model
  • Atomic models: PDB-7n00
  • Surface level: 0.005
  • Imaged by UCSF Chimera
  • Download
  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7n00
  • Imaged by Jmol
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_24095.png

Downloads & links

-
Map

FileDownload / File: emd_24095.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationAnaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 in complex with AUG-alpha
Voxel sizeX=Y=Z: 0.826 Å
Density
Contour LevelBy AUTHOR: 0.005 / Movie #1: 0.005
Minimum - Maximum-0.033018988 - 0.052078284
Average (Standard dev.)6.1926316e-06 (±0.0014943819)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 211.456 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8260.8260.826
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z211.456211.456211.456
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ260260260
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.0330.0520.000

-
Supplemental data

-
Additional map: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand...

Fileemd_24095_additional_1.map
AnnotationAnaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 in complex with AUG-alpha
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Additional map: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand...

Fileemd_24095_additional_2.map
AnnotationAnaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 in complex with AUG-alpha
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Additional map: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand...

Fileemd_24095_additional_3.map
AnnotationAnaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 in complex with AUG-alpha
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand...

Fileemd_24095_half_map_1.map
AnnotationAnaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 in complex with AUG-alpha
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand...

Fileemd_24095_half_map_2.map
AnnotationAnaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 in complex with AUG-alpha
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Sample components

-
Entire : hetero-tetrameric complex of anaplastic lymphoma kinase (ALK) wit...

EntireName: hetero-tetrameric complex of anaplastic lymphoma kinase (ALK) with Augmentor alpha
Components
  • Complex: hetero-tetrameric complex of anaplastic lymphoma kinase (ALK) with Augmentor alpha
    • Protein or peptide: ALK tyrosine kinase receptor
    • Protein or peptide: ALK and LTK ligand 2

-
Supramolecule #1: hetero-tetrameric complex of anaplastic lymphoma kinase (ALK) wit...

SupramoleculeName: hetero-tetrameric complex of anaplastic lymphoma kinase (ALK) with Augmentor alpha
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
Molecular weightExperimental: 108 kDa/nm

-
Macromolecule #1: ALK tyrosine kinase receptor

MacromoleculeName: ALK tyrosine kinase receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.377559 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: GTAPKSRNLF ERNPNKELKP GENSPRQTPI FDPTVHWLFT TCGASGPHGP TQAQCNNAYQ NSNLSVEVGS EGPLKGIQIW KVPATDTYS ISGYGAAGGK GGKNTMMRSH GVSVLGIFNL EKDDMLYILV GQQGEDACPS TNQLIQKVCI GENNVIEEEI R VNRSVHEW ...String:
GTAPKSRNLF ERNPNKELKP GENSPRQTPI FDPTVHWLFT TCGASGPHGP TQAQCNNAYQ NSNLSVEVGS EGPLKGIQIW KVPATDTYS ISGYGAAGGK GGKNTMMRSH GVSVLGIFNL EKDDMLYILV GQQGEDACPS TNQLIQKVCI GENNVIEEEI R VNRSVHEW AGGGGGGGGA TYVFKMKDGV PVPLIIAAGG GGRAYGAKTD TFHPERLENN SSVLGLNGNS GAAGGGGGWN DN TSLLWAG KSLQEGATGG HSCPQAMKKW GWETRGGFGG GGGGCSSGGG GGGYIGGNAA SNNDPEMDGE DGVSFISPLG ILY TPALKV MEGHGEVNIK HYLNCSHCEV DECHMDPESH KVICFCDHGT VLAEDGVSCI VSP

-
Macromolecule #2: ALK and LTK ligand 2

MacromoleculeName: ALK and LTK ligand 2 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.640013 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
GAEPREPADG QALLRLVVEL VQELRKHHSA EHKGLQLLGR DYALGRAEAA GLGPSPEQRV EIVPRDLRMK DKFLKHLTGP LYFSPKCSK HFHRLYHNTR DCTIPAYYKR CARLLTRLAV SPVCMEDKQ

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
Sample preparation

Concentration1 mg/mL
BufferpH: 7.4
Component:
ConcentrationName
15.0 mMHEPES
150.0 mMNaClSodium chloride
3.0 %PEG4000
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 283.15 K / Instrument: FEI VITROBOT MARK IV
Details: QUANTIFOIL R1.2/1/3 gold 300 mesh grids without glow-discharge, blotting time 3 sec., blotting force -5..

-
Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 105000
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV / Details: Gatan energy filter
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
TemperatureMin: 96.0 K / Max: 98.0 K
DetailsSerialEM coma-free alignment
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 2498 / Average exposure time: 4.2 sec. / Average electron dose: 81.0 e/Å2 / Details: 4.2 second exposure, 70 frames, total dose 81e
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

-
Image processing

Particle selectionNumber selected: 2266541 / Details: particles selection was done in cisTEM software
CTF correctionSoftware - Name: CTFFIND (ver. 4) / Details: ctfFIND4 within Relion3.0 software
Startup modelType of model: OTHER / Details: cryoSPARC ab initio
Initial angle assignmentType: OTHER / Software - Name: cryoSPARC
Details: Stochastic gradient descent (SGD) with Bayesian marginalization
Final angle assignmentType: NOT APPLICABLE / Software - Name: cryoSPARC / Details: as it is implemented in cryoSPARC
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C2 (2 fold cyclic) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.27 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Details: cryoSPARC / Number images used: 188516
FSC plot (resolution estimation)

-
Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-7n00:
Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 648-1025 in complex with AUG-alpha

+
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