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- PDB-6mx8: Crystal structure of anaplastic lymphoma kinase (ALK) bound by Br... -

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Basic information

Entry
Database: PDB / ID: 6mx8
TitleCrystal structure of anaplastic lymphoma kinase (ALK) bound by Brigatinib
ComponentsALK tyrosine kinase receptor
KeywordsTRANSFERASE / Alk Kinase / Brigatinib / Tyrosine Kinase
Function / homology
Function and homology information


response to environmental enrichment / 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 / receptor signaling protein tyrosine kinase activator activity / regulation of dopamine receptor signaling pathway ...response to environmental enrichment / 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 / receptor signaling protein tyrosine kinase activator activity / regulation of dopamine receptor signaling pathway / ALK mutants bind TKIs / swimming behavior / positive regulation of dendrite development / regulation of neuron differentiation / adult behavior / Signaling by ALK / Signaling by ALK fusions and activated point mutants / neuron development / Nuclear events stimulated by ALK signaling in cancer / negative regulation of lipid catabolic process / energy homeostasis / peptidyl-tyrosine autophosphorylation / transmembrane receptor protein tyrosine kinase activity / hippocampus development / receptor protein-tyrosine kinase / cell surface receptor protein tyrosine kinase signaling pathway / 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 / 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 / Concanavalin A-like lectin/glucanase domain superfamily / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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-6GY / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 1.96 Å
AuthorsDougan, D.R. / Zhou, T.
CitationJournal: J. Med. Chem. / Year: 2016
Title: Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.
Authors: Huang, W.S. / Liu, S. / Zou, D. / Thomas, M. / Wang, Y. / Zhou, T. / Romero, J. / Kohlmann, A. / Li, F. / Qi, J. / Cai, L. / Dwight, T.A. / Xu, Y. / Xu, R. / Dodd, R. / Toms, A. / Parillon, ...Authors: Huang, W.S. / Liu, S. / Zou, D. / Thomas, M. / Wang, Y. / Zhou, T. / Romero, J. / Kohlmann, A. / Li, F. / Qi, J. / Cai, L. / Dwight, T.A. / Xu, Y. / Xu, R. / Dodd, R. / Toms, A. / Parillon, L. / Lu, X. / Anjum, R. / Zhang, S. / Wang, F. / Keats, J. / Wardwell, S.D. / Ning, Y. / Xu, Q. / Moran, L.E. / Mohemmad, Q.K. / Jang, H.G. / Clackson, T. / Narasimhan, N.I. / Rivera, V.M. / Zhu, X. / Dalgarno, D. / Shakespeare, W.C.
History
DepositionOct 30, 2018Deposition site: RCSB / Processing site: RCSB
SupersessionDec 12, 2018ID: 5J7H
Revision 1.0Dec 12, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: ALK tyrosine kinase receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0742
Polymers34,4901
Non-polymers5841
Water1,17165
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.891, 57.502, 103.986
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 34489.711 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Chemical ChemComp-6GY / 5-chloro-N~4~-[2-(dimethylphosphoryl)phenyl]-N~2~-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine / Brigatinib / Brigatinib


Mass: 584.092 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H39ClN7O2P / Comment: inhibitor*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 65 / 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: 2.23 Å3/Da / Density % sol: 44.87 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 0.1 M TRIS HCl pH 8.5, 19-27% PEG 3350, 2 mM TCEP

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU ULTRAX 18 / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: May 26, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.96→50 Å / Num. obs: 23040 / % possible obs: 99.7 % / Redundancy: 4.2 % / Net I/σ(I): 24.32
Reflection shellResolution: 1.96→50 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0230refinement
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
HKL-2000data scaling
CNSphasing
RefinementResolution: 1.96→30 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.939 / WRfactor Rfree: 0.2294 / WRfactor Rwork: 0.1849 / FOM work R set: 0.8183 / SU B: 9.472 / SU ML: 0.124 / SU R Cruickshank DPI: 0.1695 / SU Rfree: 0.1556 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.17 / ESU R Free: 0.156 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2271 1038 4.8 %RANDOM
Rwork0.1829 ---
obs0.185 20562 93.78 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 115.02 Å2 / Biso mean: 45.539 Å2 / Biso min: 26.11 Å2
Baniso -1Baniso -2Baniso -3
1--1.14 Å20 Å2-0 Å2
2---2.59 Å2-0 Å2
3---3.73 Å2
Refinement stepCycle: final / Resolution: 1.96→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2218 0 40 65 2323
Biso mean--65.48 44.48 -
Num. residues----282
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0142323
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172063
X-RAY DIFFRACTIONr_angle_refined_deg1.3131.6833150
X-RAY DIFFRACTIONr_angle_other_deg0.8691.6214860
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0225281
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.1322.105114
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.75715391
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.0851515
X-RAY DIFFRACTIONr_chiral_restr0.0620.2297
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022592
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02403
LS refinement shellResolution: 1.96→2.011 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.287 64 -
Rwork0.274 1294 -
all-1358 -
obs--81.12 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.0811-0.54380.41813.7335-3.0232.8967-0.0578-0.0270.04390.00570.2083-0.20640.4191-0.3849-0.15050.4239-0.1714-0.26840.09930.1090.1947.596-2.53716.593
20.05010.08550.30113.60011.05692.5506-0.0214-0.00510.014-0.8119-0.21270.2015-0.3526-0.29640.2340.22540.0328-0.10040.16280.00260.083-2.18910.5212.383
30.5428-0.26550.3611.46890.59741.5345-0.11480.12460.06730.0508-0.0279-0.2917-0.2490.18870.14270.0908-0.0253-0.0370.14380.05750.159.614.7097.228
40.38420.44370.10930.71250.31110.2173-0.0370.03260.1128-0.01920.04580.10360.0428-0.0164-0.00890.1340.0053-0.04410.1330.04920.11495.32719.49716.176
50.33310.2722-0.34520.79420.110.6383-0.09790.05680.0341-0.12750.13510.06670.05810.0341-0.03720.1176-0.007-0.04360.15740.00520.108711.90318.09816.264
60.93730.1428-0.51050.5651-0.16790.2987-0.0113-0.06390.0713-0.02560.0442-0.00170.01030.0568-0.03290.1122-0.0046-0.02430.178-0.0040.077223.56627.35921.238
71.5054-0.45120.29733.3466-0.89760.27790.0045-0.2478-0.0168-0.04270.12140.34710.0218-0.0392-0.12590.12720.0380.01930.1072-0.02080.12469.41432.70129.526
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1094 - 1112
2X-RAY DIFFRACTION2A1113 - 1144
3X-RAY DIFFRACTION3A1145 - 1173
4X-RAY DIFFRACTION4A1174 - 1243
5X-RAY DIFFRACTION5A1244 - 1292
6X-RAY DIFFRACTION6A1293 - 1375
7X-RAY DIFFRACTION7A1376 - 1400

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