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- PDB-4dce: Crystal structure of human anaplastic lymphoma kinase in complex ... -

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Basic information

Entry
Database: PDB / ID: 4dce
TitleCrystal structure of human anaplastic lymphoma kinase in complex with a piperidine-carboxamide inhibitor
ComponentsALK tyrosine kinase receptor
KeywordsTransferase/Inhibitor / receptor tyrosine kinase / inhibitor / NPM-ALK / EML4-ALK / Transferase-Inhibitor complex
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 / neuron development / negative regulation of lipid catabolic process / phosphorylation / peptidyl-tyrosine autophosphorylation / cell surface receptor protein tyrosine kinase signaling pathway / energy homeostasis / transmembrane receptor protein tyrosine kinase activity / hippocampus development / receptor protein-tyrosine kinase / Signaling by ALK fusions and activated point mutants / heparin binding / positive regulation of NF-kappaB transcription factor activity / 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
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 / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / LDL receptor-like superfamily / : ...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 / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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
Chem-0JF / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.03 Å
AuthorsWhittington, D.A. / Epstein, L.F. / Chen, H.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Rapid development of piperidine carboxamides as potent and selective anaplastic lymphoma kinase inhibitors.
Authors: Bryan, M.C. / Whittington, D.A. / Doherty, E.M. / Falsey, J.R. / Cheng, A.C. / Emkey, R. / Brake, R.L. / Lewis, R.T.
History
DepositionJan 17, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 8, 2012Provider: repository / Type: Initial release
Revision 1.1May 9, 2012Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ALK tyrosine kinase receptor
B: ALK tyrosine kinase receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,1194
Polymers75,1362
Non-polymers9832
Water5,170287
1
A: ALK tyrosine kinase receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0602
Polymers37,5681
Non-polymers4921
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: ALK tyrosine kinase receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0602
Polymers37,5681
Non-polymers4921
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.612, 104.819, 57.817
Angle α, β, γ (deg.)90.000, 90.150, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 37568.133 Da / Num. of mol.: 2 / Fragment: Kinase domain, unp residues 1078-1410 / Mutation: C1097S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALK / Plasmid: pFastBac1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Chemical ChemComp-0JF / (3S)-N-(4-methylbenzyl)-1-{2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}piperidine-3-carboxamide


Mass: 491.582 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H33N5O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 287 / Source method: isolated from a natural source / Formula: H2O

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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: 2.08 Å3/Da / Density % sol: 40.91 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 27% PEG 5000 MME, 100 mM MES, 200 mM ammonium sulfate, 5 mM dithiothreitol, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Mar 14, 2009
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.03→50 Å / Num. all: 39890 / Num. obs: 39292 / % possible obs: 98.5 % / Observed criterion σ(I): -3 / Redundancy: 2.3 % / Biso Wilson estimate: 31.7 Å2 / Rmerge(I) obs: 0.048 / Χ2: 1.213 / Net I/σ(I): 11
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.03-2.120.4935911.204190.3
2.1-2.192.20.38938721.223198.2
2.19-2.292.20.27939911.202199.7
2.29-2.412.30.20339621.266199.9
2.41-2.562.30.15639781.2781100
2.56-2.762.30.10440001.2731100
2.76-3.032.30.06939641.227199.8
3.03-3.472.40.03839521.17199.7
3.47-4.372.40.02840031.102199.4
4.37-502.30.01939791.184198.2

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Translation4 Å1000 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
EPMRphasing
REFMACrefinement
PDB_EXTRACT3.1data extraction
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: apo ALK (unpublished)

Resolution: 2.03→38.83 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.925 / WRfactor Rfree: 0.2602 / WRfactor Rwork: 0.2086 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.8166 / SU B: 5.13 / SU ML: 0.143 / SU R Cruickshank DPI: 0.2259 / SU Rfree: 0.1919 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.226 / ESU R Free: 0.192 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.256 1972 5 %RANDOM
Rwork0.2082 ---
obs0.2107 39180 98.61 %-
all-39732 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 67.61 Å2 / Biso mean: 34.4147 Å2 / Biso min: 16.85 Å2
Baniso -1Baniso -2Baniso -3
1--0.6 Å20 Å2-0.24 Å2
2--1.79 Å20 Å2
3----1.19 Å2
Refinement stepCycle: LAST / Resolution: 2.03→38.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4499 0 72 287 4858
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0224686
X-RAY DIFFRACTIONr_angle_refined_deg1.0271.9936353
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2365564
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.24223.99203
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.16415781
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.241530
X-RAY DIFFRACTIONr_chiral_restr0.0690.2688
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.023562
X-RAY DIFFRACTIONr_nbd_refined0.1820.22180
X-RAY DIFFRACTIONr_nbtor_refined0.3020.23235
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1190.2284
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1740.280
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1260.211
X-RAY DIFFRACTIONr_mcbond_it0.79922951
X-RAY DIFFRACTIONr_mcangle_it1.34234639
X-RAY DIFFRACTIONr_scbond_it1.31531992
X-RAY DIFFRACTIONr_scangle_it2.19761714
LS refinement shellResolution: 2.03→2.083 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.311 154 -
Rwork0.271 2476 -
all-2630 -
obs--89.21 %

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