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- PDB-7n00: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand... -

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Basic information

Entry
Database: PDB / ID: 7n00
TitleAnaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 648-1025 in complex with AUG-alpha
Components
  • ALK and LTK ligand 2
  • ALK tyrosine kinase receptor
KeywordsTRANSFERASE / Anaplastic lymphoma kinase / Receptor tyrosine kinases / RTK / FAM150 / DE NOVO PROTEIN
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 / Signaling by LTK / regulation of neuron differentiation / positive regulation of dendrite development / Signaling by ALK / phosphorylation / response to stress / adult behavior / neuron development / negative regulation of lipid catabolic process / peptidyl-tyrosine autophosphorylation / energy homeostasis / transmembrane receptor protein tyrosine kinase activity / cell surface receptor protein tyrosine kinase signaling pathway / hippocampus development / cytokine activity / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / positive regulation of neuron projection development / receptor tyrosine kinase binding / positive regulation of NF-kappaB transcription factor activity / 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 / receptor complex / positive regulation of ERK1 and ERK2 cascade / 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. / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Low-density lipoprotein receptor domain class A ...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. / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Low-density lipoprotein receptor domain class A / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.27 Å
AuthorsReshetnyak, A.V. / Myasnikov, A.G. / Rossi, P. / Miller, D.J. / Kalodimos, C.G.
Funding support United States, 1items
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, 2021Deposition site: RCSB / Processing site: RCSB
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Assembly

Deposited unit
A: ALK tyrosine kinase receptor
C: ALK tyrosine kinase receptor
B: ALK and LTK ligand 2
D: ALK and LTK ligand 2


Theoretical massNumber of molelcules
Total (without water)108,0354
Polymers108,0354
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: light scattering
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area5640 Å2
ΔGint-19 kcal/mol
Surface area33710 Å2

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Components

#1: Protein ALK tyrosine kinase receptor / Anaplastic lymphoma kinase


Mass: 39377.559 Da / Num. of mol.: 2 / Mutation: C66Y
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): C+ RIPL
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Protein ALK and LTK ligand 2 / Augmentor alpha / AUG-alpha / Protein FAM150B


Mass: 14640.013 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALKAL2, FAM150B, UNQ542/PRO1097 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): C+ RIPL / References: UniProt: Q6UX46
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: hetero-tetrameric complex of anaplastic lymphoma kinase (ALK) with Augmentor alpha
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 108 kDa/nm / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.4
Buffer component
IDConc.NameBuffer-ID
115 mMHEPES1
2150 mMNaCl1
33 %PEG40001
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 283.15 K
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 imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS / Details: SerialEM coma-free alignment
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 1500 nm / Nominal defocus min: 500 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 98 K / Temperature (min): 96 K
Image recordingAverage exposure time: 4.2 sec. / Electron dose: 81 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 2498 / Details: 4.2 second exposure, 70 frames, total dose 81e
EM imaging opticsEnergyfilter name: GIF Bioquantum / Details: Gatan energy filter / Energyfilter slit width: 20 eV

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Processing

SoftwareName: PHENIX / Version: 1.19_4092: / Classification: refinement
EM software
IDNameVersionCategory
1cisTEM1.0.0particle selection
2SerialEMimage acquisition
4CTFFIND4CTF correction
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
12cryoSPARC3D reconstruction
13PHENIXmodel refinement
CTF correctionDetails: ctfFIND4 within Relion3.0 software / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2266541 / Details: particles selection was done in cisTEM software
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 2.27 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 188516 / Algorithm: FOURIER SPACE / Details: cryoSPARC / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0045953
ELECTRON MICROSCOPYf_angle_d0.4868056
ELECTRON MICROSCOPYf_dihedral_angle_d14.762072
ELECTRON MICROSCOPYf_chiral_restr0.046836
ELECTRON MICROSCOPYf_plane_restr0.0041077

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