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- PDB-4ctc: Structure of the Human Anaplastic Lymphoma Kinase in Complex with... -

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Entry
Database: PDB / ID: 4ctc
TitleStructure of the Human Anaplastic Lymphoma Kinase in Complex with the inhibitor 7-amino-3-cyclopropyl-12-fluoro-1,10,16-trimethyl-16,17- dihydro-1H-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecin-15(10H)-one
ComponentsALK TYROSINE KINASE RECEPTOR
KeywordsTRANSFERASE / INHIBITOR
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 / phosphorylation / positive regulation of dendrite development / regulation of neuron differentiation / peptidyl-tyrosine autophosphorylation / Signaling by ALK / response to stress / adult behavior / neuron development / negative regulation of lipid catabolic process / energy homeostasis / transmembrane receptor protein tyrosine kinase activity / cell surface receptor protein tyrosine kinase signaling pathway / hippocampus development / positive regulation of NF-kappaB transcription factor activity / receptor protein-tyrosine kinase / 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. / Low-density lipoprotein receptor domain class A / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / 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. / Low-density lipoprotein receptor domain class A / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / 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
Chem-J99 / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.03 Å
AuthorsMcTigue, M.A. / Deng, Y.L. / Liu, W. / Brooun, A. / Stewart, A.E.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Discovery of (10R)-7-Amino-12-Fluoro-2,10,16-Trimethyl-15-Oxo-10,15,16,17-Tetrahydro-2H-8,4-(Metheno)Pyrazolo[4,3-H][2,5,11]Benzoxadiazacyclotetradecine-3-Carbonitrile (Pf-06463922), a ...Title: Discovery of (10R)-7-Amino-12-Fluoro-2,10,16-Trimethyl-15-Oxo-10,15,16,17-Tetrahydro-2H-8,4-(Metheno)Pyrazolo[4,3-H][2,5,11]Benzoxadiazacyclotetradecine-3-Carbonitrile (Pf-06463922), a Macrocyclic Inhibitor of Alk/Ros1 with Pre-Clinical Brain Exposure and Broad Spectrum Potency Against Alk-Resistant Mutations.
Authors: Johnson, T.W. / Richardson, P.F. / Bailey, S. / Brooun, A. / Burke, B.J. / Collins, M.R. / Cui, J.J. / Deal, J.G. / Deng, Y.L. / Dinh, D.M. / Engstrom, L.D. / He, M. / Hoffman, J.E. / ...Authors: Johnson, T.W. / Richardson, P.F. / Bailey, S. / Brooun, A. / Burke, B.J. / Collins, M.R. / Cui, J.J. / Deal, J.G. / Deng, Y.L. / Dinh, D.M. / Engstrom, L.D. / He, M. / Hoffman, J.E. / Hoffman, R.L. / Huang, Q. / Kath, J. / Kania, R.S. / Lam, H. / Lam, J.L. / Le, P.T. / Lingardo, L. / Liu, W. / Mctigue, M.A. / Palmer, C.L. / Sach, N.W. / Smeal, T. / Smith, G.L. / Stewart, A.E. / Timofeevski, S.L. / Zhu, H. / Zhu, J. / Zou, H.Y. / Edwards, M.P.
History
DepositionMar 12, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 28, 2014Provider: repository / Type: Initial release
Revision 1.1Jun 25, 2014Group: Database references / Other
Revision 1.2May 8, 2019Group: Data collection / Experimental preparation / Other
Category: database_PDB_rev / database_PDB_rev_record ...database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.method / _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval
Revision 1.3Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)37,3312
Polymers36,9091
Non-polymers4211
Water4,720262
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.810, 57.100, 104.710
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 / CD246


Mass: 36909.355 Da / Num. of mol.: 1 / Fragment: TYROSINE KINASE DOMAIN, RESIDUES 1093-1411
Source method: isolated from a genetically manipulated source
Details: NONPHOSPHORYLATED / Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBAC / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Chemical ChemComp-J99 / (10R)-7-amino-3-cyclopropyl-12-fluoro-1,10,16-trimethyl-16,17-dihydro-1H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecin-15(10H)-one


Mass: 421.467 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H24FN5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 262 / 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: 2.1 Å3/Da / Density % sol: 41 % / Description: NONE
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: HANGING DROP VAPOR DIFFUSION AT 13 DEGREES C. EQUAL VOLUMES OF PURIFIED PROTEIN SOLUTION (APPROXIMATELY 13-15 MG/ML)CONTAINING 0.001M INHIBITOR COMPOUND WERE COMBINED WITH A SOLUTION ...Details: HANGING DROP VAPOR DIFFUSION AT 13 DEGREES C. EQUAL VOLUMES OF PURIFIED PROTEIN SOLUTION (APPROXIMATELY 13-15 MG/ML)CONTAINING 0.001M INHIBITOR COMPOUND WERE COMBINED WITH A SOLUTION CONTAINING: 0.15M AMMONIUM SULFATE, 9-10.5% MONOMETHYLETHER PEG5K AND 0.1M MES IN THE PH RANGE 5.3-6.5

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Data collection

DiffractionMean temperature: 87 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 1
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 3, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.03→52.35 Å / Num. obs: 20763 / % possible obs: 99.9 % / Observed criterion σ(I): 1 / Redundancy: 6.5 % / Biso Wilson estimate: 27.91 Å2 / Rmerge(I) obs: 0.12 / Net I/σ(I): 10.2
Reflection shellResolution: 2.03→2.08 Å / Redundancy: 6.4 % / Rmerge(I) obs: 0.58 / Mean I/σ(I) obs: 2.7 / % possible all: 99.6

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
CCP4data reduction
SCALAdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2XP2

2xp2


Resolution: 2.03→52.35 Å / Cor.coef. Fo:Fc: 0.9305 / Cor.coef. Fo:Fc free: 0.9298 / SU R Cruickshank DPI: 0.192 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.215 / SU Rfree Blow DPI: 0.16 / SU Rfree Cruickshank DPI: 0.153
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2157 1062 5.13 %RANDOM
Rwork0.1926 ---
obs0.1938 20712 99.93 %-
Displacement parametersBiso mean: 30.78 Å2
Baniso -1Baniso -2Baniso -3
1-2.4751 Å20 Å20 Å2
2--6.0059 Å20 Å2
3----8.481 Å2
Refinement stepCycle: LAST / Resolution: 2.03→52.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2265 0 31 262 2558
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0092353HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.033193HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d810SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes57HARMONIC2
X-RAY DIFFRACTIONt_gen_planes359HARMONIC5
X-RAY DIFFRACTIONt_it2353HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.02
X-RAY DIFFRACTIONt_other_torsion17.47
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion300SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3017SEMIHARMONIC4
LS refinement shellResolution: 2.03→2.14 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2393 172 5.82 %
Rwork0.1981 2784 -
all0.2004 2956 -
obs--99.93 %

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