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- PDB-3b2w: Crystal structure of pyrimidine amide 11 bound to Lck -

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Basic information

Entry
Database: PDB / ID: 3b2w
TitleCrystal structure of pyrimidine amide 11 bound to Lck
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 / Phosphorylation / 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 / 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
Chem-9NH / Tyrosine-protein kinase Lck
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsHuang, X.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: N-(3-(phenylcarbamoyl)arylpyrimidine)-5-carboxamides as potent and selective inhibitors of Lck: structure, synthesis and SAR.
Authors: Deak, H.L. / Newcomb, J.R. / Nunes, J.J. / Boucher, C. / Cheng, A.C. / DiMauro, E.F. / Epstein, L.F. / Gallant, P. / Hodous, B.L. / Huang, X. / Lee, J.H. / Patel, V.F. / Schneider, S. / Turci, S.M. / Zhu, X.
History
DepositionOct 19, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 18, 2007Provider: 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

Downloads & links

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Assembly

Deposited unit
A: Proto-oncogene tyrosine-protein kinase LCK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,6822
Polymers32,0591
Non-polymers6241
Water2,432135
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.18, 75.19, 47.11
Angle α, β, γ (deg.)90.0, 112.35, 90.0
Int Tables number4
Space group name H-MP1211

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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: 32058.656 Da / Num. of mol.: 1 / Fragment: Lck kinase domain: Residues 226-502
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LCK / Culture collection (production host): Insect cell / Production host: unidentified baculovirus
References: UniProt: P06239, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-9NH / N-[5-({[2-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-2-methylphenyl]-4-methoxy-2-[(4-piperazin-1-ylphenyl)amino]pyrimidine-5-carboxamide


Mass: 623.601 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H29F4N7O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 135 / 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: 2.31 Å3/Da / Density % sol: 46.72 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 1.0 M LiCl, 20% PEG 6000, pH 6.0, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→30 Å / Num. obs: 12320 / % possible obs: 94.3 % / Observed criterion σ(I): -3 / Rmerge(I) obs: 0.078 / Net I/σ(I): 10
Reflection shellResolution: 2.3→2.38 Å / Rmerge(I) obs: 0.288 / Mean I/σ(I) obs: 3.6 / % possible all: 81.6

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
AMoREphasing
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1QPC

1qpc


Resolution: 2.3→30 Å / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.308 -RANDOM
Rwork0.23 --
obs0.23 12320 -
Refinement stepCycle: LAST / Resolution: 2.3→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2068 0 45 135 2248
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.0107
X-RAY DIFFRACTIONc_angle_deg1.5

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