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Yorodumi- PDB-7mzw: Anaplastic lymphoma kinase (ALK) extracellular ligand binding reg... -
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-Basic information
Entry | Database: PDB / ID: 7mzw | ||||||
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Title | Anaplastic lymphoma kinase (ALK) extracellular ligand binding region 673-1025 | ||||||
Components | ALK tyrosine kinase receptor | ||||||
Keywords | TRANSFERASE / Anaplastic lymphoma kinase / Receptor tyrosine kinases / RTK / FAM150 / LTK / DE NOVO PROTEIN | ||||||
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 / peptidyl-tyrosine autophosphorylation / neuron development / transmembrane receptor protein tyrosine kinase activity / negative regulation of lipid catabolic process / energy homeostasis / cell surface receptor protein tyrosine kinase signaling pathway / phosphorylation / 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 | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | SOLUTION NMR / molecular dynamics | ||||||
Authors | Rossi, P. / Sowaileh, M. / Reshetnyak, A.V. / Kalodimos, C.G. | ||||||
Funding support | United States, 1items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7mzw.cif.gz | 2.1 MB | Display | PDBx/mmCIF format |
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PDB format | pdb7mzw.ent.gz | 1.9 MB | Display | PDB format |
PDBx/mmJSON format | 7mzw.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7mzw_validation.pdf.gz | 396.3 KB | Display | wwPDB validaton report |
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Full document | 7mzw_full_validation.pdf.gz | 508.7 KB | Display | |
Data in XML | 7mzw_validation.xml.gz | 126.3 KB | Display | |
Data in CIF | 7mzw_validation.cif.gz | 176.1 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/mz/7mzw ftp://data.pdbj.org/pub/pdb/validation_reports/mz/7mzw | HTTPS FTP |
-Related structure data
Related structure data | 7mzxC 7mzyC 7mzzC 7n00C C: citing same article (ref.) |
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Similar structure data | |
Other databases |
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-Links
-Assembly
Deposited unit |
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NMR ensembles |
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-Components
#1: Protein | Mass: 36452.293 Da / Num. of mol.: 1 / Fragment: Ligand binding region, residues 673-1025 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: ALK / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) References: UniProt: Q9UM73, receptor protein-tyrosine kinase |
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-Experimental details
-Experiment
Experiment | Method: SOLUTION NMR | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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NMR experiment |
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-Sample preparation
Details |
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Sample |
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Sample conditions | Ionic strength: 170 mM / Label: conditions_1 / pH: 7 / Pressure: 1 atm / Temperature: 308 K |
-NMR measurement
NMR spectrometer |
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-Processing
NMR software |
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Refinement | Method: molecular dynamics / Software ordinal: 1 / Details: restrained MD in explicit H2O bath | ||||||||||||||||||||||||||||||||||||||||||||
NMR representative | Selection criteria: lowest energy | ||||||||||||||||||||||||||||||||||||||||||||
NMR ensemble | Conformer selection criteria: target function / Conformers calculated total number: 100 / Conformers submitted total number: 20 |