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- PDB-7ls0: Structure of the Human ALK GRD bound to AUG -

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Basic information

Entry
Database: PDB / ID: 7ls0
TitleStructure of the Human ALK GRD bound to AUG
ComponentsALK tyrosine kinase receptor fused with ALK and LTK ligand 2
KeywordsTRANSFERASE/TRANSFERASE ACTIVATOR / glycine rich domain / neuroblastoma / cancer / oncogene / SIGNALING PROTEIN / TRANSFERASE / TRANSFERASE-TRANSFERASE ACTIVATOR complex
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
CITRIC ACID / ALK and LTK ligand 2 / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.05 Å
AuthorsStayrook, S. / Li, T. / Klein, D.E.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)K22 CA215821 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA248532 United States
CitationJournal: Nature / Year: 2021
Title: Structural basis for ligand reception by anaplastic lymphoma kinase.
Authors: Li, T. / Stayrook, S.E. / Tsutsui, Y. / Zhang, J. / Wang, Y. / Li, H. / Proffitt, A. / Krimmer, S.G. / Ahmed, M. / Belliveau, O. / Walker, I.X. / Mudumbi, K.C. / Suzuki, Y. / Lax, I. / ...Authors: Li, T. / Stayrook, S.E. / Tsutsui, Y. / Zhang, J. / Wang, Y. / Li, H. / Proffitt, A. / Krimmer, S.G. / Ahmed, M. / Belliveau, O. / Walker, I.X. / Mudumbi, K.C. / Suzuki, Y. / Lax, I. / Alvarado, D. / Lemmon, M.A. / Schlessinger, J. / Klein, D.E.
History
DepositionFeb 17, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 24, 2021Provider: repository / Type: Initial release
Revision 1.1Dec 8, 2021Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Dec 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
Revision 1.3Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: ALK tyrosine kinase receptor fused with ALK and LTK ligand 2
B: ALK tyrosine kinase receptor fused with ALK and LTK ligand 2
C: ALK tyrosine kinase receptor fused with ALK and LTK ligand 2
D: ALK tyrosine kinase receptor fused with ALK and LTK ligand 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)190,1047
Polymers189,4994
Non-polymers6053
Water00
1
A: ALK tyrosine kinase receptor fused with ALK and LTK ligand 2
C: ALK tyrosine kinase receptor fused with ALK and LTK ligand 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)95,1344
Polymers94,7492
Non-polymers3842
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: ALK tyrosine kinase receptor fused with ALK and LTK ligand 2
D: ALK tyrosine kinase receptor fused with ALK and LTK ligand 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)94,9713
Polymers94,7492
Non-polymers2211
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.262, 177.754, 94.855
Angle α, β, γ (deg.)90.000, 104.800, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
ALK tyrosine kinase receptor fused with ALK and LTK ligand 2 / Anaplastic lymphoma kinase / Augmentor alpha / AUG-alpha / Protein FAM150B


Mass: 47374.711 Da / Num. of mol.: 4
Fragment: Glycine-rich domain residues 678-1030 fused with ALK and LTK ligand 2 residues 85-152
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALK, ALKAL2, FAM150B, UNQ542/PRO1097 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q9UM73, UniProt: Q6UX46, receptor protein-tyrosine kinase
#2: Chemical ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H8O7
#3: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.85 Å3/Da / Density % sol: 56.84 % / Description: plate
Crystal growTemperature: 289.15 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: Citrate pH 5.5, 20% PEG 3000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 1.0332 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 9, 2019 / Details: undulator
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 3.05→49.77 Å / Num. obs: 40292 / % possible obs: 99.6 % / Observed criterion σ(I): -3 / Redundancy: 3.3 % / Biso Wilson estimate: 85 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.166 / Net I/σ(I): 3.6
Reflection shellResolution: 3.05→3.12 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.783 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 2737 / CC1/2: 0.4 / % possible all: 87.1

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Processing

Software
NameVersionClassification
PHENIXdev_3915refinement
XDS20200417data reduction
SCALA0.7.4data scaling
PDB_EXTRACT3.27data extraction
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7LRZ

7lrz


Resolution: 3.05→49.77 Å / SU ML: 0.5 / Cross valid method: THROUGHOUT / σ(F): 1.41 / Phase error: 32.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2882 1945 4.83 %
Rwork0.2378 38347 -
obs0.2403 40292 99.47 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 203.83 Å2 / Biso mean: 76.1415 Å2 / Biso min: 19.57 Å2
Refinement stepCycle: final / Resolution: 3.05→49.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10632 0 40 0 10672
Biso mean--120.01 --
Num. residues----1446
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00510912
X-RAY DIFFRACTIONf_angle_d0.76614741
X-RAY DIFFRACTIONf_chiral_restr0.0521510
X-RAY DIFFRACTIONf_plane_restr0.0041960
X-RAY DIFFRACTIONf_dihedral_angle_d11.2961552
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.05-3.120.36961430.33982593273695
3.12-3.210.37411170.322427552872100
3.21-3.30.3461340.304627882922100
3.3-3.410.30791430.300327032846100
3.41-3.530.33681540.296427152869100
3.53-3.670.34061450.277127572902100
3.67-3.840.31141310.237427362867100
3.84-4.040.26731310.218627512882100
4.04-4.290.27051430.19727502893100
4.29-4.620.24171320.179527462878100
4.62-5.090.28011270.185827742901100
5.09-5.830.25151290.212727542883100
5.83-7.340.29521610.241827582919100
7.34-49.770.26231550.23862767292299

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