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- PDB-4c3f: Structure of Lck in complex with a compound discovered by Virtual... -

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Basic information

Entry
Database: PDB / ID: 4c3f
TitleStructure of Lck in complex with a compound discovered by Virtual Fragment Linking
ComponentsTYROSINE-PROTEIN KINASE LCK
KeywordsTRANSFERASE
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 / FLT3 signaling through SRC family kinases / intracellular zinc ion homeostasis / CD4 receptor binding / Nef Mediated CD4 Down-regulation / Nef and signal transduction / positive regulation of heterotypic cell-cell adhesion ...regulation of lymphocyte activation / positive regulation of leukocyte cell-cell adhesion / Fc-gamma receptor signaling pathway / CD28 co-stimulation / FLT3 signaling through SRC family kinases / intracellular zinc ion homeostasis / CD4 receptor binding / Nef Mediated CD4 Down-regulation / Nef and signal transduction / positive regulation of heterotypic cell-cell adhesion / Interleukin-2 signaling / CD28 dependent Vav1 pathway / Regulation of KIT signaling / leukocyte migration / CTLA4 inhibitory signaling / protein serine/threonine phosphatase activity / phospholipase activator activity / CD8 receptor binding / pericentriolar material / positive regulation of T cell receptor signaling pathway / Translocation of ZAP-70 to Immunological synapse / Phosphorylation of CD3 and TCR zeta chains / PECAM1 interactions / phospholipase binding / CD28 dependent PI3K/Akt signaling / hemopoiesis / RHOH GTPase cycle / Generation of second messenger molecules / immunological synapse / T cell differentiation / PD-1 signaling / phosphatidylinositol 3-kinase binding / T cell receptor binding / peptidyl-tyrosine autophosphorylation / positive regulation of intrinsic apoptotic signaling pathway / cell surface receptor protein tyrosine kinase signaling pathway / GPVI-mediated activation cascade / release of sequestered calcium ion into cytosol / T cell costimulation / phosphotyrosine residue binding / SH2 domain 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 / Constitutive Signaling by Aberrant PI3K in Cancer / positive regulation of T cell activation / Downstream TCR signaling / DAP12 signaling / PIP3 activates AKT signaling / T cell receptor signaling pathway / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / protein phosphatase binding / intracellular signal transduction / response to xenobiotic stimulus / membrane raft / protein phosphorylation / innate immune response / signaling receptor binding / 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 ...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 / 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-7KW / Tyrosine-protein kinase Lck
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.72 Å
AuthorsCowan-Jacob, S.W. / Rummel, G. / Stark, W.
CitationJournal: J. Med. Chem. / Year: 2013
Title: Efficient search of chemical space: navigating from fragments to structurally diverse chemotypes.
Authors: Wassermann, A.M. / Kutchukian, P.S. / Lounkine, E. / Luethi, T. / Hamon, J. / Bocker, M.T. / Malik, H.A. / Cowan-Jacob, S.W. / Glick, M.
History
DepositionAug 23, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 23, 2013Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2014Group: Database references
Revision 1.2Dec 14, 2016Group: Data collection / Other
Revision 1.3Apr 4, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.4Feb 27, 2019Group: Data collection / Database references / Experimental preparation
Category: citation / exptl_crystal_grow ...citation / exptl_crystal_grow / pdbx_database_proc / struct_biol
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _exptl_crystal_grow.temp
Revision 1.5Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / 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 / _pdbx_database_status.status_code_sf / _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

Downloads & links

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Assembly

Deposited unit
A: TYROSINE-PROTEIN KINASE LCK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,9702
Polymers30,6561
Non-polymers3131
Water6,395355
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)58.088, 44.596, 120.254
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 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: 30656.152 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 237-501 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P06239, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-7KW / N-phenyl-4-(5-phenyl-1H-pyrazol-4-yl)pyrimidin-2-amine


Mass: 313.356 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H15N5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 355 / 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: 44.49 % / Description: NONE
Crystal growTemperature: 277 K
Details: 16 % PEG 8000, 0.1 M NA CACODYLATE PH 6.5, 0.2 M MG ACETATE, 4 C

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E / Wavelength: 1.5418
DetectorType: RIGAKU CCD / Detector: CCD / Date: Oct 14, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.72→41.81 Å / Num. obs: 30169 / % possible obs: 88.7 % / Observed criterion σ(I): 0 / Redundancy: 6.3 % / Biso Wilson estimate: 27.3 Å2 / Rmerge(I) obs: 0.03 / Net I/σ(I): 32.51
Reflection shellResolution: 1.72→1.77 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.24 / Mean I/σ(I) obs: 4.38 / % possible all: 46.3

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Processing

Software
NameVersionClassification
REFMAC5.7.0029refinement
XDSdata reduction
XSCALEdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3MPM

3mpm


Resolution: 1.72→41.78 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.938 / SU B: 2.316 / SU ML: 0.075 / Cross valid method: THROUGHOUT / ESU R: 0.118 / ESU R Free: 0.118 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2196 1508 5 %RANDOM
Rwork0.17741 ---
obs0.17953 28658 88.74 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 25.946 Å2
Baniso -1Baniso -2Baniso -3
1--0.4 Å20 Å20 Å2
2--0.19 Å20 Å2
3---0.21 Å2
Refinement stepCycle: LAST / Resolution: 1.72→41.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2078 0 24 355 2457
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0192191
X-RAY DIFFRACTIONr_bond_other_d0.0010.022069
X-RAY DIFFRACTIONr_angle_refined_deg1.6651.9782974
X-RAY DIFFRACTIONr_angle_other_deg0.89834756
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1985263
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.49923.529102
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.48415380
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.1131517
X-RAY DIFFRACTIONr_chiral_restr0.1060.2322
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0212463
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02503
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.72→1.765 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.289 55 -
Rwork0.259 1051 -
obs--44.94 %

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