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- PDB-7mzw: Anaplastic lymphoma kinase (ALK) extracellular ligand binding reg... -

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Basic information

Entry
Database: PDB / ID: 7mzw
TitleAnaplastic lymphoma kinase (ALK) extracellular ligand binding region 673-1025
ComponentsALK tyrosine kinase receptor
KeywordsTRANSFERASE / 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 / adult behavior / Signaling by ALK / 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 / 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 / regulation of apoptotic process / protein tyrosine kinase activity / protein autophosphorylation / receptor complex / phosphorylation / signal transduction / protein-containing complex / extracellular exosome / ATP binding / identical protein binding / plasma membrane
Similarity search - Function
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 ...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 / Tyrosine protein kinases specific active-site signature. / Concanavalin A-like lectin/glucanase domain superfamily / 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 tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodSOLUTION NMR / molecular dynamics
AuthorsRossi, P. / Sowaileh, M. / Reshetnyak, A.V. / 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
Revision 1.0Dec 8, 2021Provider: repository / Type: Initial release
Revision 1.1Dec 15, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ALK tyrosine kinase receptor


Theoretical massNumber of molelcules
Total (without water)36,4521
Polymers36,4521
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: light scattering
TypeNameSymmetry operationNumber
identity operation1_5551
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)20 / 100target function
RepresentativeModel #1lowest energy

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Components

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


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

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDSample stateSpectrometer-IDType
121isotropic22D 1H-15N HSQC
132isotropic32D 1H-13C HSQC aromatic
142isotropic12D 1H-13C HMQC
151isotropic23D CBCA(CO)NH
1171isotropic23D HN(CO)CA
1161isotropic23D HNCO
1151isotropic23D HN(CA)CB
1141isotropic23D HCACO
1131isotropic23D 1H-15N NOESY
1122isotropic13D CmCmHm NOESY
1112isotropic23D HNH NOESY
1102isotropic33D HaCaHa NOESY
192isotropic33D CaCmHm NOESY
182isotropic23D CmNH NOESY
172isotropic23D NCmHm NOESY

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Sample preparation

Details
TypeSolution-IDContentsDetailsLabelSolvent system
solution1300 uM [U-100% 13C; U-100% 15N; U-100% 2H] Anaplastic lymphoma kinase ALK extracellular domain 673-1025, 20 mM sodium phosphate, 150 mM sodium chloride, 0.1 % sodium azide, 90% H2O/10% D2Otriple labeled U-2H,13C,15Ntriple_labeled90% H2O/10% D2O
solution2400 uM U-2H,15N-1H13C_AILMTV_1H,13C-FY (Ce1,2) Anaplastic lymphoma kinase ALK extracellular domain 673-1025, 20 mM sodium phosphate, 150 mM sodium chloride, 0.1 % sodium azide, 90% H2O/10% D2Omethyl aromatic labeled U-2H,15N-1H13C_AILMTV_1H,13C-FY (Ce1,2)methyl_aromatic_labeled90% H2O/10% D2O
Sample
Conc. (mg/ml)ComponentIsotopic labelingSolution-ID
300 uMAnaplastic lymphoma kinase ALK extracellular domain 673-1025[U-100% 13C; U-100% 15N; U-100% 2H]1
20 mMsodium phosphatenatural abundance1
150 mMsodium chloridenatural abundance1
0.1 %sodium azidenatural abundance1
400 uMAnaplastic lymphoma kinase ALK extracellular domain 673-1025U-2H,15N-1H13C_AILMTV_1H,13C-FY (Ce1,2)2
20 mMsodium phosphatenatural abundance2
150 mMsodium chloridenatural abundance2
0.1 %sodium azidenatural abundance2
Sample conditionsIonic strength: 170 mM / Label: conditions_1 / pH: 7.0 / Pressure: 1 atm / Temperature: 308 K

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NMR measurement

NMR spectrometer
TypeManufacturerModelField strength (MHz)Spectrometer-ID
Bruker AVANCE NEOBrukerAVANCE NEO11001
Bruker AVANCE NEOBrukerAVANCE NEO8502
Bruker AVANCE NEOBrukerAVANCE NEO7003

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Processing

NMR software
NameVersionDeveloperClassification
CNSBrunger, Adams, Clore, Gros, Nilges and Readrefinement
CYANAGuntert, Mumenthaler and Wuthrichstructure calculation
I-PINELee, Bahrami, Dashti, Eghbalnia, Tonelli, Westler and Markleychemical shift assignment
PINEBahrami, Markley, Assadi, and Eghbalniapeak picking
TopSpin4.06Bruker Biospincollection
NMRFAM-SPARKYleepeak picking
TALOS-NSHEN AND BAXgeometry optimization
NMRPipeDelaglio, Grzesiek, Vuister, Zhu, Pfeifer and Baxprocessing
PdbStattejero and montelionedata analysis
PSVSBhattacharya and Montelionedata analysis
RefinementMethod: molecular dynamics / Software ordinal: 1 / Details: restrained MD in explicit H2O bath
NMR representativeSelection criteria: lowest energy
NMR ensembleConformer selection criteria: target function / Conformers calculated total number: 100 / Conformers submitted total number: 20

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