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- EMDB-24095: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand... -

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Entry
Database: EMDB / ID: EMD-24095
TitleAnaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 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
KeywordsAnaplastic lymphoma kinase / Receptor tyrosine kinases / RTK / FAM150 / DE NOVO PROTEIN / TRANSFERASE
Function / homology
Function and homology information


positive regulation of ERK5 cascade / 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 ...positive regulation of ERK5 cascade / 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 / transmembrane receptor protein tyrosine kinase activator activity / ALK mutants bind TKIs / swimming behavior / phosphorylation / Signaling by LTK / 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 / cytokine activity / hippocampus development / positive regulation of NF-kappaB transcription factor activity / positive regulation of neuron projection development / receptor protein-tyrosine kinase / receptor tyrosine kinase binding / 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 / positive regulation of ERK1 and ERK2 cascade / receptor complex / 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 / : / 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. ...ALK and LTK ligand 1/2 / ALK and LTK ligand 1/2 / : / 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 / 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-
UpdateMay 28, 2025-
Current statusMay 28, 2025Processing site: RCSB / Status: Released

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Structure visualization

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

emd_24095.png

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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
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 256 pix.
= 211.456 Å		0.83 Å/pix.
x 256 pix.
= 211.456 Å		0.83 Å/pix.
x 256 pix.
= 211.456 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.826 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.005 / Movie #1: 0.005
Minimum - Maximum-0.033018988 - 0.052078284
Average (Standard dev.)0.0000061926316 (±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

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Supplemental data

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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

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Slices (1/2)
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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

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Histogram

Histogram (log scale)

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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

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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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)

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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

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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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

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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)
Molecular weightTheoretical: 108 kDa/nm

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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

UniProtKB: ALK tyrosine kinase receptor

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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

UniProtKB: ALK and LTK ligand 2

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1 mg/mL
BufferpH: 7.4
Component:
ConcentrationName
15.0 mMHEPES
150.0 mMNaCl
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..

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Electron microscopy

MicroscopeFEI TITAN KRIOS
TemperatureMin: 96.0 K / Max: 98.0 K
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV / Details: Gatan energy filter
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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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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 / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: cryoSPARC ab initio
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
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
FSC plot (resolution estimation)

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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

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