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- PDB-2ofv: crystal structure of aminoquinazoline 1 bound to Lck -

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Basic information

Entry
Database: PDB / ID: 2ofv
Titlecrystal structure of aminoquinazoline 1 bound to Lck
ComponentsProto-oncogene tyrosine-protein kinase LCK
KeywordsTRANSFERASE / Lck / Kinase domain
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 / Nef and signal transduction / CD4 receptor binding / Nef Mediated CD4 Down-regulation / 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 / Nef and signal transduction / CD4 receptor binding / Nef Mediated CD4 Down-regulation / 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 / CD28 dependent PI3K/Akt signaling / phospholipase binding / hemopoiesis / RHOH GTPase cycle / Generation of second messenger molecules / immunological synapse / T cell differentiation / PD-1 signaling / phosphatidylinositol 3-kinase binding / positive regulation of intrinsic apoptotic signaling pathway / T cell receptor binding / peptidyl-tyrosine autophosphorylation / 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 / non-specific protein-tyrosine kinase / B cell receptor signaling pathway / 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 / PIP3 activates AKT signaling / DAP12 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 / protein phosphorylation / membrane raft / 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-242 / Tyrosine-protein kinase Lck
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsHuang, X.
CitationJournal: J.Med.Chem. / Year: 2006
Title: Discovery of Aminoquinazolines as Potent, Orally Bioavailable Inhibitors of Lck: Synthesis, SAR, and in Vivo Anti-Inflammatory Activity
Authors: DiMauro, E.F. / Newcomb, J. / Nunes, J.J. / Bemis, J.E. / Boucher, C. / Buchanan, J.L. / Buckner, W.H. / Cee, V.J. / Chai, L. / Deak, H.L. / Epstein, L.F. / Faust, T. / Gallant, P. / Geuns- ...Authors: DiMauro, E.F. / Newcomb, J. / Nunes, J.J. / Bemis, J.E. / Boucher, C. / Buchanan, J.L. / Buckner, W.H. / Cee, V.J. / Chai, L. / Deak, H.L. / Epstein, L.F. / Faust, T. / Gallant, P. / Geuns-Meyer, S.D. / Gore, A. / Gu, Y. / Henkle, B. / Hodous, B.L. / Hsieh, F. / Huang, X. / Kim, J.L. / Lee, J.H. / Martin, M.W. / Masse, C.E. / 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. / White, R.D. / Zhao, H. / Zhu, L. / Zhu, X.
History
DepositionJan 4, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 27, 2007Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Aug 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_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: Proto-oncogene tyrosine-protein kinase LCK
B: Proto-oncogene tyrosine-protein kinase LCK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,9624
Polymers64,1172
Non-polymers8452
Water4,882271
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)142.66, 66.89, 78.51
Angle α, β, γ (deg.)90, 112.00, 90
Int Tables number5
Space group name H-MC121
DetailsThe Biological Assembly is a monomer.

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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.: 2 / Fragment: Lck kinase domain, residues 231-497
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LCK / Production host: Insect Cell
References: UniProt: P06239, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-242 / 3-(2-AMINOQUINAZOLIN-6-YL)-4-METHYL-N-[3-(TRIFLUOROMETHYL)PHENYL]BENZAMIDE / AMINOQUINAZOLINE 1


Mass: 422.402 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H17F3N4O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 271 / 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: 2.71 Å3/Da / Density % sol: 54.56 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.3 M MgAcetate, 5-12.5% PEG8000, pH 6.5, 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 4 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→30 Å / Num. obs: 41290 / % possible obs: 89.1 % / Observed criterion σ(I): -3 / Rmerge(I) obs: 0.091 / Net I/σ(I): 16.2
Reflection shellResolution: 2→2.07 Å / Rmerge(I) obs: 0.281 / Mean I/σ(I) obs: 2.5 / % possible all: 55.4

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Processing

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

1qpc


Resolution: 2→30 Å / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.301 -RANDOM
Rwork0.274 --
obs-41284 -
Refinement stepCycle: LAST / Resolution: 2→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3878 0 62 271 4211
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.01
X-RAY DIFFRACTIONc_angle_deg1.46

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