[English] 日本語
![](img/lk-miru.gif)
- EMDB-24095: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand... -
+
Open data
-
Basic information
Entry | Database: EMDB / ID: EMD-24095 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Title | Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 648-1025 in complex with AUG-alpha | |||||||||
![]() | Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 in complex with AUG-alpha | |||||||||
![]() |
| |||||||||
Function / homology | ![]() 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 / ALK mutants bind TKIs / swimming behavior / positive regulation of dendrite development / Signaling by LTK / regulation of neuron differentiation / Signaling by ALK / adult behavior / transmembrane receptor protein tyrosine kinase activator activity / neuron development / negative regulation of lipid catabolic process / energy homeostasis / peptidyl-tyrosine autophosphorylation / cell surface receptor protein tyrosine kinase signaling pathway / transmembrane receptor protein tyrosine kinase activity / cytokine activity / hippocampus development / receptor protein-tyrosine kinase / receptor tyrosine kinase binding / positive regulation of neuron projection development / Signaling by ALK fusions and activated point mutants / phosphorylation / heparin binding / positive regulation of NF-kappaB transcription factor activity / regulation of cell population proliferation / regulation of apoptotic process / protein tyrosine kinase activity / protein autophosphorylation / 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 | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.27 Å | |||||||||
![]() | Myasnikov AG / Reshetnyak AV / Kalodimos CG | |||||||||
Funding support | ![]()
| |||||||||
![]() | ![]() 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 |
|
-
Structure visualization
Movie |
![]() |
---|---|
Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
-
Downloads & links
-EMDB archive
Map data | ![]() | 48.6 MB | ![]() | |
---|---|---|---|---|
Header (meta data) | ![]() ![]() | 27.1 KB 27.1 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() ![]() | 9.7 KB 9.1 KB | Display Display | ![]() |
Images | ![]() | 74.8 KB | ||
Others | ![]() ![]() ![]() ![]() ![]() | 59.9 MB 32.1 MB 5 MB 48.6 MB 48.6 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7n00MC ![]() 7mzwC ![]() 7mzxC ![]() 7mzyC ![]() 7mzzC M: atomic model generated by this map C: citing same article ( |
---|---|
Similar structure data | |
EM raw data | ![]() Data size: 10.2 TB Data #1: Unaligned multi-frame micrographs of 2:2 ALK:AugAlpha complex [micrographs - multiframe] Data #2: Aligned single-frame micrographs of 2:2 ALK:AugAlpha complex [micrographs - single frame]) |
-
Links
EMDB pages | ![]() ![]() |
---|---|
Related items in Molecule of the Month |
-
Map
File | ![]() | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 in complex with AUG-alpha | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.826 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
|
-Supplemental data
-Additional map: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand...
File | emd_24095_additional_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 in complex with AUG-alpha | ||||||||||||
Projections & Slices |
| ||||||||||||
Density Histograms |
-Additional map: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand...
File | emd_24095_additional_2.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 in complex with AUG-alpha | ||||||||||||
Projections & Slices |
| ||||||||||||
Density Histograms |
-Additional map: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand...
File | emd_24095_additional_3.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 in complex with AUG-alpha | ||||||||||||
Projections & Slices |
| ||||||||||||
Density Histograms |
-Half map: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand...
File | emd_24095_half_map_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 in complex with AUG-alpha | ||||||||||||
Projections & Slices |
| ||||||||||||
Density Histograms |
-Half map: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand...
File | emd_24095_half_map_2.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 in complex with AUG-alpha | ||||||||||||
Projections & Slices |
| ||||||||||||
Density Histograms |
-
Sample components
-Entire : hetero-tetrameric complex of anaplastic lymphoma kinase (ALK) wit...
Entire | Name: hetero-tetrameric complex of anaplastic lymphoma kinase (ALK) with Augmentor alpha |
---|---|
Components |
|
-Supramolecule #1: hetero-tetrameric complex of anaplastic lymphoma kinase (ALK) wit...
Supramolecule | Name: hetero-tetrameric complex of anaplastic lymphoma kinase (ALK) with Augmentor alpha type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
---|---|
Source (natural) | Organism: ![]() |
Recombinant expression | Organism: ![]() ![]() |
Molecular weight | Experimental: 108 kDa/nm |
-Macromolecule #1: ALK tyrosine kinase receptor
Macromolecule | Name: 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: ![]() |
Molecular weight | Theoretical: 39.377559 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: 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
Macromolecule | Name: ALK and LTK ligand 2 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO |
---|---|
Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 14.640013 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: GAEPREPADG QALLRLVVEL VQELRKHHSA EHKGLQLLGR DYALGRAEAA GLGPSPEQRV EIVPRDLRMK DKFLKHLTGP LYFSPKCSK HFHRLYHNTR DCTIPAYYKR CARLLTRLAV SPVCMEDKQ |
-Experimental details
-Structure determination
Method | cryo EM |
---|---|
![]() | single particle reconstruction |
Aggregation state | particle |
-
Sample preparation
Concentration | 1 mg/mL | ||||||||
---|---|---|---|---|---|---|---|---|---|
Buffer | pH: 7.4 Component:
| ||||||||
Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY | ||||||||
Vitrification | Cryogen 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
Microscope | FEI TITAN KRIOS |
---|---|
Temperature | Min: 96.0 K / Max: 98.0 K |
Specialist optics | Energy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV / Details: Gatan energy filter |
Details | SerialEM coma-free alignment |
Image recording | Film 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 beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | C2 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 stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
+
Image processing
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: RIGID BODY FIT |
---|---|
Output model | ![]() PDB-7n00: |