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- PDB-6pdj: Tyrosine-protein kinase LCK bound to Compound 11 -

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Basic information

Entry
Database: PDB / ID: 6pdj
TitleTyrosine-protein kinase LCK bound to Compound 11
ComponentsTyrosine-protein kinase Lck
KeywordsSIGNALING PROTEIN/INHIBITOR / inhibitor / SIGNALING PROTEIN / SIGNALING PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


regulation of lymphocyte activation / positive regulation of leukocyte cell-cell adhesion / Fc-gamma receptor signaling pathway / CD28 co-stimulation / intracellular zinc ion homeostasis / FLT3 signaling through SRC family kinases / CD4 receptor binding / Nef Mediated CD4 Down-regulation / Nef and signal transduction / Interleukin-2 signaling ...regulation of lymphocyte activation / positive regulation of leukocyte cell-cell adhesion / Fc-gamma receptor signaling pathway / CD28 co-stimulation / intracellular zinc ion homeostasis / FLT3 signaling through SRC family kinases / CD4 receptor binding / Nef Mediated CD4 Down-regulation / Nef and signal transduction / Interleukin-2 signaling / CD28 dependent Vav1 pathway / positive regulation of heterotypic cell-cell adhesion / protein serine/threonine phosphatase activity / Regulation of KIT signaling / CTLA4 inhibitory signaling / leukocyte migration / phospholipase activator activity / positive regulation of T cell receptor signaling pathway / pericentriolar material / Translocation of ZAP-70 to Immunological synapse / Phosphorylation of CD3 and TCR zeta chains / PECAM1 interactions / phospholipase binding / CD28 dependent PI3K/Akt signaling / RHOH GTPase cycle / hemopoiesis / Generation of second messenger molecules / immunological synapse / T cell differentiation / CD8 receptor binding / PD-1 signaling / phosphatidylinositol 3-kinase binding / positive regulation of intrinsic apoptotic signaling pathway / peptidyl-tyrosine autophosphorylation / release of sequestered calcium ion into cytosol / GPVI-mediated activation cascade / T cell costimulation / extrinsic component of cytoplasmic side of plasma membrane / phosphotyrosine residue binding / SH2 domain binding / T cell receptor binding / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / Signaling by SCF-KIT / platelet activation / peptidyl-tyrosine phosphorylation / cell surface receptor protein tyrosine kinase signaling pathway / activation of cysteine-type endopeptidase activity involved in apoptotic process / Constitutive Signaling by Aberrant PI3K in Cancer / positive regulation of T cell activation / Downstream TCR signaling / PIP3 activates AKT signaling / DAP12 signaling / ATPase binding / T cell receptor signaling pathway / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein phosphatase binding / protein tyrosine kinase activity / intracellular signal transduction / response to xenobiotic stimulus / membrane raft / protein phosphorylation / signaling receptor binding / innate immune response / protein kinase binding / extracellular exosome / ATP binding / identical protein binding / plasma membrane / cytosol
Similarity search - Function
Lck, SH3 domain / Tyrosine-protein kinase Lck, SH2 domain / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily ...Lck, SH3 domain / Tyrosine-protein kinase Lck, SH2 domain / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / 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
NICKEL (II) ION / Chem-ODJ / Tyrosine-protein kinase Lck
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.81 Å
AuthorsCritton, D.A.
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Discovery of Pyridazinone and Pyrazolo[1,5-a]pyridine Inhibitors of C-Terminal Src Kinase.
Authors: O'Malley, D.P. / Ahuja, V. / Fink, B. / Cao, C. / Wang, C. / Swanson, J. / Wee, S. / Gavai, A.V. / Tokarski, J. / Critton, D. / Paiva, A.A. / Johnson, B.M. / Szapiel, N. / Xie, D.
History
DepositionJun 19, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 9, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Oct 11, 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 / pdbx_struct_conn_angle / software / struct_conn / struct_conn_type
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _software.name / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry / _struct_conn_type.id
Revision 1.3Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase Lck
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3196
Polymers33,3921
Non-polymers9275
Water5,242291
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.016, 74.163, 104.527
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Tyrosine-protein kinase Lck / Leukocyte C-terminal Src kinase / LSK / Lymphocyte cell-specific protein-tyrosine kinase / Protein ...Leukocyte C-terminal Src kinase / LSK / Lymphocyte cell-specific protein-tyrosine kinase / Protein YT16 / Proto-oncogene Lck / T cell-specific protein-tyrosine kinase / p56-LCK


Mass: 33391.996 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LCK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P06239, non-specific protein-tyrosine kinase

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Non-polymers , 5 types, 296 molecules

#2: Chemical ChemComp-ODJ / N-{4-[(6-methoxypyrazolo[1,5-a]pyridine-3-carbonyl)amino]-3-methylphenyl}-1-methyl-1H-indazole-3-carboxamide


Mass: 454.481 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H22N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CXS / 3-CYCLOHEXYL-1-PROPYLSULFONIC ACID / CAPS (buffer)


Mass: 221.317 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H19NO3S / Comment: pH buffer*YM
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-NI / NICKEL (II) ION / Nickel


Mass: 58.693 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ni
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 291 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.44 Å3/Da / Density % sol: 49.68 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 10.5
Details: 1.5 M ammonium sulfate, 120 mM lithium chloride, 10 mM nickel(II) chloride, 100 mM CAPS pH 10.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 19, 2015 / Details: Kirkpatrick-Baez mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.81→38.984 Å / Num. obs: 136656 / % possible obs: 89.8 % / Redundancy: 6.46 % / Biso Wilson estimate: 21.04 Å2 / Rpim(I) all: 0.066 / Net I/σ(I): 9.7
Reflection shellResolution: 1.81→1.975 Å / Num. unique obs: 6062 / Rpim(I) all: 0.464

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1QPJ

1qpj


Resolution: 1.81→26.13 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.923 / SU R Cruickshank DPI: 0.163 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.184 / SU Rfree Blow DPI: 0.161 / SU Rfree Cruickshank DPI: 0.153
RfactorNum. reflection% reflectionSelection details
Rfree0.217 1039 4.9 %RANDOM
Rwork0.167 ---
obs0.169 21199 69.6 %-
Displacement parametersBiso max: 109.52 Å2 / Biso mean: 27.25 Å2 / Biso min: 5.33 Å2
Baniso -1Baniso -2Baniso -3
1-1.961 Å20 Å20 Å2
2---0.7288 Å20 Å2
3----1.2322 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: final / Resolution: 1.81→26.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2178 0 59 291 2528
Biso mean--33.89 36.9 -
Num. residues----274
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d778SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes414HARMONIC5
X-RAY DIFFRACTIONt_it2300HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion290SEMIHARMONIC5
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_contact2898SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2300HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3128HARMONIC21.06
X-RAY DIFFRACTIONt_omega_torsion3.57
X-RAY DIFFRACTIONt_other_torsion17.28
LS refinement shellResolution: 1.81→1.9 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2558 20 4.72 %
Rwork0.2082 404 -
all0.2105 424 -
obs--11.13 %
Refinement TLS params.Method: refined / Origin x: 2.7944 Å / Origin y: -6.6579 Å / Origin z: -16.1656 Å
111213212223313233
T-0.0199 Å20.0005 Å2-0.0071 Å2--0.0235 Å20.004 Å2---0.0629 Å2
L0.2834 °2-0.0109 °2-0.0678 °2-1.7413 °20.3743 °2--0.3761 °2
S-0.0159 Å °-0.0866 Å °-0.0353 Å °0.2056 Å °0.0174 Å °-0.083 Å °0.0374 Å °0.0291 Å °-0.0016 Å °
Refinement TLS groupSelection details: { A|* }

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