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- PDB-4tt7: Crystal structure of human ALK with a covalent modification -

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Basic information

Entry
Database: PDB / ID: 4tt7
TitleCrystal structure of human ALK with a covalent modification
ComponentsALK tyrosine kinase receptor
KeywordsTRANSFERASE / ATP-BINDING / RECEPTOR
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 / 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 / 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 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 / signal transduction / protein-containing complex / extracellular exosome / ATP binding / identical protein binding / plasma membrane
Similarity search - Function
: / 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 ...: / 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
1-THIOETHANESULFONIC ACID / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsBadger, J. / Sridhar, V. / Chie-Leon, B. / Nienaber, V.L. / Hausheer, F.H.
CitationJournal: Onco Targets Ther / Year: 2015
Title: Novel covalent modification of human anaplastic lymphoma kinase (ALK) and potentiation of crizotinib-mediated inhibition of ALK activity by BNP7787.
Authors: Parker, A.R. / Petluru, P.N. / Nienaber, V.L. / Zhao, M. / Ayala, P.Y. / Badger, J. / Chie-Leon, B. / Sridhar, V. / Logan, C. / Kochat, H. / Hausheer, F.H.
History
DepositionJun 19, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 11, 2015Provider: repository / Type: Initial release
Revision 1.1Mar 18, 2015Group: Structure summary
Revision 1.2Jun 3, 2015Group: Database references
Revision 1.3Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / entity_src_gen / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_oper_list / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_oper_list.symmetry_operation / _refine_hist.number_atoms_solvent / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_ligand / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein
Revision 1.4Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ALK tyrosine kinase receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,2416
Polymers36,7701
Non-polymers4715
Water2,864159
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1060 Å2
ΔGint4 kcal/mol
Surface area13400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.535, 57.157, 104.216
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 36770.191 Da / Num. of mol.: 1 / Fragment: UNP residues 1095-1410
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALK / Cell line (production host): SP9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Chemical ChemComp-COM / 1-THIOETHANESULFONIC ACID


Mass: 142.197 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O3S2
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 159 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.09 Å3/Da / Density % sol: 41.07 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 2 uL of 17 mg/mL protein (50 mM Bicine pH 8.4, 150 mM NaCl, 5 mM DTT) with 2 uL of 0.1 M TRIS hydrochloride, 0.2 M Sodium acetate trihydrate, 30% w/v Polyethylene glycol 4,000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.9774 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 9, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 2.1→46.2 Å / Num. obs: 18384 / % possible obs: 98.8 % / Redundancy: 5.6 % / Rmerge(I) obs: 0.135 / Net I/σ(I): 10.1
Reflection shellResolution: 2.1→2.21 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.621 / Mean I/σ(I) obs: 2.8 / % possible all: 97.5

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Processing

SoftwareName: REFMAC / Version: 5.5.0072 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2XP2

2xp2


Resolution: 2.1→46.2 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.908 / SU B: 4.675 / SU ML: 0.127 / Cross valid method: THROUGHOUT / ESU R: 0.233 / ESU R Free: 0.196 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.24403 938 5.1 %RANDOM
Rwork0.19201 ---
obs0.19458 17402 98.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.256 Å2
Baniso -1Baniso -2Baniso -3
1--0.86 Å20 Å20 Å2
2---0.6 Å20 Å2
3---1.46 Å2
Refinement stepCycle: 1 / Resolution: 2.1→46.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2243 0 26 159 2428
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0222344
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1971.9783175
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2145290
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.30323.8100
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.07415383
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.1841515
X-RAY DIFFRACTIONr_chiral_restr0.080.2350
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211754
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.81521456
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.482.52349
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.7083888
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.7824.5824
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.1→2.154 Å /
RfactorNum. reflection
Rfree0.285 79
Rwork0.232 1245

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