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- PDB-3bys: co-crystal structure of Lck and aminopyrimidine amide 10b -

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Basic information

Entry
Database: PDB / ID: 3bys
Titleco-crystal structure of Lck and aminopyrimidine amide 10b
ComponentsProto-oncogene tyrosine-protein kinase LCK
KeywordsTRANSFERASE / Lck / Kinase domain / Alternative splicing / ATP-binding / Chromosomal rearrangement / Cytoplasm / Disease mutation / Host-virus interaction / Lipoprotein / Membrane / Myristate / Nucleotide-binding / Palmitate / Phosphoprotein / Proto-oncogene / SH2 domain / SH3 domain / Tyrosine-protein kinase
Function / homology
Function and homology information


regulation of lymphocyte activation / positive regulation of leukocyte cell-cell adhesion / CD27 signaling pathway / Fc-gamma receptor signaling pathway / FLT3 signaling through SRC family kinases / CD4 receptor binding / Nef Mediated CD4 Down-regulation / intracellular zinc ion homeostasis / Nef and signal transduction / positive regulation of heterotypic cell-cell adhesion ...regulation of lymphocyte activation / positive regulation of leukocyte cell-cell adhesion / CD27 signaling pathway / Fc-gamma receptor signaling pathway / FLT3 signaling through SRC family kinases / CD4 receptor binding / Nef Mediated CD4 Down-regulation / intracellular zinc ion homeostasis / Nef and signal transduction / positive regulation of heterotypic cell-cell adhesion / Co-stimulation by CD28 / Interleukin-2 signaling / CD28 dependent Vav1 pathway / Regulation of KIT signaling / leukocyte migration / phospholipase activator activity / Co-inhibition by CTLA4 / protein serine/threonine phosphatase activity / CD8 receptor binding / pericentriolar material / Translocation of ZAP-70 to Immunological synapse / Phosphorylation of CD3 and TCR zeta chains / positive regulation of T cell receptor signaling pathway / phospholipase binding / PECAM1 interactions / hemopoiesis / RHOH GTPase cycle / Generation of second messenger molecules / T cell differentiation / immunological synapse / Co-inhibition by PD-1 / CD28 dependent PI3K/Akt signaling / phosphatidylinositol 3-kinase binding / T cell receptor binding / peptidyl-tyrosine autophosphorylation / positive regulation of intrinsic apoptotic signaling pathway / GPVI-mediated activation cascade / T cell costimulation / release of sequestered calcium ion into cytosol / phosphotyrosine residue binding / SH2 domain binding / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / T cell activation / cell surface receptor protein tyrosine kinase signaling pathway / non-membrane spanning protein tyrosine kinase activity / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / Signaling by SCF-KIT / peptidyl-tyrosine phosphorylation / platelet activation / positive regulation of T cell activation / Constitutive Signaling by Aberrant PI3K in Cancer / DAP12 signaling / Downstream TCR 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 / protein phosphorylation / membrane raft / response to xenobiotic stimulus / signaling receptor binding / protein kinase binding / extracellular exosome / ATP binding / identical protein binding / plasma membrane / cytosol / cytoplasm
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 / SH2 domain superfamily / Src homology 3 domains ...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 / SH2 domain superfamily / Src homology 3 domains / 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 / 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-AM5 / Tyrosine-protein kinase Lck
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsHuang, X.
CitationJournal: J.Med.Chem. / Year: 2008
Title: Structure-guided design of aminopyrimidine amides as potent, selective inhibitors of lymphocyte specific kinase: synthesis, structure-activity relationships, and inhibition of in vivo T cell activation.
Authors: DiMauro, E.F. / Newcomb, J. / Nunes, J.J. / Bemis, J.E. / Boucher, C. / Chai, L. / Chaffee, S.C. / Deak, H.L. / Epstein, L.F. / Faust, T. / Gallant, P. / Gore, A. / Gu, Y. / Henkle, B. / ...Authors: DiMauro, E.F. / Newcomb, J. / Nunes, J.J. / Bemis, J.E. / Boucher, C. / Chai, L. / Chaffee, S.C. / Deak, H.L. / Epstein, L.F. / Faust, T. / Gallant, P. / Gore, A. / Gu, Y. / Henkle, B. / Hsieh, F. / Huang, X. / Kim, J.L. / Lee, J.H. / Martin, M.W. / McGowan, D.C. / Metz, D. / Mohn, D. / Morgenstern, K.A. / Oliveira-dos-Santos, A. / Patel, V.F. / Powers, D. / Rose, P.E. / Schneider, S. / Tomlinson, S.A. / Tudor, Y.Y. / Turci, S.M. / Welcher, A.A. / Zhao, H. / Zhu, L. / Zhu, X.
History
DepositionJan 16, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 16, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Aug 30, 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: Proto-oncogene tyrosine-protein kinase LCK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,6472
Polymers32,0581
Non-polymers5901
Water91951
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)44.00, 73.70, 101.47
Angle α, β, γ (deg.)90, 90, 90
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Proto-oncogene tyrosine-protein kinase LCK / p56-LCK / Lymphocyte cell-specific protein-tyrosine kinase / LSK / T cell-specific protein-tyrosine kinase


Mass: 32057.672 Da / Num. of mol.: 1 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LCK / Cell line (production host): Insect Cell / Production host: Baculovirus
References: UniProt: P06239, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-AM5 / 4-methyl-N~3~-(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-5-yl)-N~1~-[3-(trifluoromethyl)phenyl]benzene-1,3-dicarboxamide


Mass: 589.611 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H30F3N7O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 51 / 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: 2.57 Å3/Da / Density % sol: 52.07 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.2 M Sodium Citrate, 20%(v/v) Isopropanol, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→30 Å / Num. all: 17369 / Num. obs: 16334 / % possible obs: 94.2 % / Observed criterion σ(I): -3 / Redundancy: 3 % / Rmerge(I) obs: 0.069 / Net I/σ(I): 14
Reflection shellResolution: 2.2→2.28 Å / Rmerge(I) obs: 0.233 / Mean I/σ(I) obs: 5.8 / % possible all: 79.9

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Processing

Software
NameClassification
CrystalCleardata collection
AMoREphasing
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1QPC

1qpc


Resolution: 2.2→30 Å / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.284 825 RANDOM
Rwork0.246 --
all-17369 -
obs-16334 -
Refinement stepCycle: LAST / Resolution: 2.2→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2064 0 43 51 2158
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.01
X-RAY DIFFRACTIONc_angle_deg1.54

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