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- PDB-3mpm: LCK complexed with a pyrazolopyrimidine -

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Basic information

Entry
Database: PDB / ID: 3mpm
TitleLCK complexed with a pyrazolopyrimidine
ComponentsTyrosine-protein kinase Lck
KeywordsTRANSFERASE / 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 / intracellular zinc ion homeostasis / FLT3 signaling through SRC family kinases / 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 / intracellular zinc ion homeostasis / FLT3 signaling through SRC family kinases / 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 / CTLA4 inhibitory signaling / protein serine/threonine phosphatase activity / leukocyte migration / 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 / RHOH GTPase cycle / hemopoiesis / Generation of second messenger molecules / immunological synapse / T cell differentiation / PD-1 signaling / phosphatidylinositol 3-kinase binding / T cell receptor binding / positive regulation of intrinsic apoptotic signaling pathway / peptidyl-tyrosine autophosphorylation / release of sequestered calcium ion into cytosol / extrinsic component of cytoplasmic side of plasma membrane / GPVI-mediated activation cascade / cell surface receptor protein tyrosine kinase signaling pathway / 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 / activation of cysteine-type endopeptidase activity involved in apoptotic process / Downstream TCR signaling / positive regulation of T cell activation / PIP3 activates AKT signaling / DAP12 signaling / T cell receptor signaling pathway / ATPase binding / 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 / 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 / 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-5LK / Tyrosine-protein kinase Lck
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.95 Å
AuthorsCowan-Jacob, S.W. / Rummel, G.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: New pyrazolo[1,5a]pyrimidines as orally active inhibitors of Lck.
Authors: Gommermann, N. / Buehlmayer, P. / von Matt, A. / Breitenstein, W. / Masuya, K. / Pirard, B. / Furet, P. / Cowan-Jacob, S.W. / Weckbecker, G.
History
DepositionApr 27, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 2, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Mar 7, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.source
Revision 1.3Oct 6, 2021Group: Database references / Derived calculations / Category: database_2 / 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
Revision 1.4Feb 21, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)31,1213
Polymers30,6561
Non-polymers4652
Water4,648258
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)58.073, 44.624, 120.967
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 / Proto-oncogene Lck / Lymphocyte cell-specific protein-tyrosine kinase / p56-LCK / LSK / T cell- ...Proto-oncogene Lck / Lymphocyte cell-specific protein-tyrosine kinase / p56-LCK / LSK / T cell-specific protein-tyrosine kinase


Mass: 30656.152 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 237-501 / Mutation: D364N
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
#2: Chemical ChemComp-5LK / 4-{(6R,7R)-7-amino-3-[3-(4-methylpiperazin-1-yl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl}phenol


Mass: 402.492 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H26N6O
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 258 / 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: 2.56 Å3/Da / Density % sol: 51.89 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 7
Details: 9.5 % PEG 8000, 0.1 M HEPES PH 7.0, 7% ETHYLENEGLYCOL, VAPOR DIFFUSION, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E DW / Wavelength: 1.54178 / Wavelength: 1.5418 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Jan 12, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
11.541781
21.54181
ReflectionResolution: 1.95→52.34 Å / Num. obs: 23680 / % possible obs: 98.6 % / Observed criterion σ(F): 0 / Redundancy: 3.48 % / Biso Wilson estimate: 33.7 Å2 / Rmerge(I) obs: 0.047 / Net I/σ(I): 16.03
Reflection shellResolution: 1.95→2.03 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.3 / Mean I/σ(I) obs: 3.91 / Num. unique all: 1532 / % possible all: 90.3

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Processing

Software
NameClassification
MAR345dtbdata collection
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.95→52.34 Å / SU B: 6.496 / SU ML: 0.098 / Cross valid method: THROUGHOUT / ESU R Free: 0.137 / Stereochemistry target values: Engh & Huber / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21297 1184 5 %RANDOM
Rwork0.17001 ---
obs0.17223 22495 99.45 %-
Displacement parametersBiso mean: 28.942 Å2
Baniso -1Baniso -2Baniso -3
1--0.08 Å20 Å20 Å2
2--0.6 Å20 Å2
3----0.52 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.137 Å0.144 Å
Refinement stepCycle: LAST / Resolution: 1.95→52.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2085 0 34 258 2377
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONr_bond_refined_d0.015
X-RAY DIFFRACTIONr_angle_refined_deg1.326
X-RAY DIFFRACTIONr_chiral_restr0.086
X-RAY DIFFRACTIONr_gen_planes_refined0.006
X-RAY DIFFRACTIONr_nbtor_refined0.304
LS refinement shellResolution: 1.95→1.996 Å
RfactorNum. reflection% reflection
Rfree0.3 80 -
Rwork0.205 --
obs-1532 94.27 %

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