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- PDB-4joa: Crystal Structure of Human Anaplastic Lymphoma Kinase in complex ... -

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Basic information

Entry
Database: PDB / ID: 4joa
TitleCrystal Structure of Human Anaplastic Lymphoma Kinase in complex with 7-azaindole based inhibitor
ComponentsALK tyrosine kinase receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Anaplastic Lymphoma Kinase / TRANSFERASE-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 / LDL receptor-like superfamily / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / : ...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 / 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-3DK / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsHosahalli, S. / Krishnamurthy, N.R. / Lakshminarasimhan, A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Discovery of 7-azaindole based anaplastic lymphoma kinase (ALK) inhibitors: wild type and mutant (L1196M) active compounds with unique binding mode
Authors: Gummadi, V.R. / Rajagopalan, S. / Looi, C.Y. / Paydar, M. / Renukappa, G.A. / Ainan, B.R. / Krishnamurthy, N.R. / Panigrahi, S.K. / Mahasweta, K. / Raghuramachandran, S. / Rajappa, M. / ...Authors: Gummadi, V.R. / Rajagopalan, S. / Looi, C.Y. / Paydar, M. / Renukappa, G.A. / Ainan, B.R. / Krishnamurthy, N.R. / Panigrahi, S.K. / Mahasweta, K. / Raghuramachandran, S. / Rajappa, M. / Ramanathan, A. / Lakshminarasimhan, A. / Ramachandra, M. / Wong, P.F. / Mustafa, M.R. / Nanduri, S. / Hosahalli, S.
History
DepositionMar 18, 2013Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jul 17, 2013Provider: repository / Type: Initial release
Revision 1.1Apr 23, 2014Group: Database references
Revision 1.2Nov 8, 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_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

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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)39,0322
Polymers38,6411
Non-polymers3901
Water46826
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.794, 56.503, 104.536
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: 38641.324 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, UNP residues 1072-1410 / Mutation: S1281G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALK / Plasmid: pFastBacHTB / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9UM73, receptor protein-tyrosine kinase
#2: Chemical ChemComp-3DK / 3-[1-(2,5-difluorobenzyl)-1H-pyrazol-4-yl]-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine


Mass: 390.389 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H16F2N6
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 26 / 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: 1.98 Å3/Da / Density % sol: 37.86 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1M Hepes pH 7.5, 20% PEG 8000, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE
RadiationMonochromator: Mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. obs: 8211 / % possible obs: 92 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 4.1 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 11.1
Reflection shellResolution: 2.7→2.8 Å / Redundancy: 4 % / Rmerge(I) obs: 0.473 / Mean I/σ(I) obs: 2.6 / Num. unique all: 799 / % possible all: 91.9

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.2.0001refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3LCS

3lcs


Resolution: 2.7→50 Å / Cor.coef. Fo:Fc: 0.902 / Cor.coef. Fo:Fc free: 0.862 / SU B: 14.506 / SU ML: 0.292 / Cross valid method: THROUGHOUT / ESU R Free: 0.431 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28964 370 4.8 %RANDOM
Rwork0.25109 ---
obs0.2529 7358 87.02 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 46.394 Å2
Baniso -1Baniso -2Baniso -3
1--2.31 Å20 Å20 Å2
2---2.06 Å20 Å2
3---4.37 Å2
Refinement stepCycle: LAST / Resolution: 2.7→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1946 0 29 26 2001
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0222010
X-RAY DIFFRACTIONr_bond_other_d0.0010.021837
X-RAY DIFFRACTIONr_angle_refined_deg1.1811.9912728
X-RAY DIFFRACTIONr_angle_other_deg0.71534255
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0395242
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.31323.6984
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.30515322
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.8491513
X-RAY DIFFRACTIONr_chiral_restr0.0550.2300
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.022194
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02400
X-RAY DIFFRACTIONr_nbd_refined0.190.2458
X-RAY DIFFRACTIONr_nbd_other0.1580.21914
X-RAY DIFFRACTIONr_nbtor_other0.0780.21150
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1170.249
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0930.28
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1170.221
X-RAY DIFFRACTIONr_mcbond_it0.2841.51279
X-RAY DIFFRACTIONr_mcbond_other0.0291.5498
X-RAY DIFFRACTIONr_mcangle_it0.49421996
X-RAY DIFFRACTIONr_scbond_it0.3773850
X-RAY DIFFRACTIONr_scangle_it0.6164.5732
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.548 36
Rwork0.314 538

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