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- PDB-3kmm: Structure of human LCK kinase with a small molecule inhibitor -

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Basic information

Entry
Database: PDB / ID: 3kmm
TitleStructure of human LCK kinase with a small molecule inhibitor
ComponentsProto-oncogene tyrosine-protein kinase LCK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TYROSINE KINASE / ATP-binding / Kinase / Nucleotide-binding / Phosphoprotein / Transferase / Tyrosine-protein kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
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-LHL / Tyrosine-protein kinase Lck
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsGraves, B.J. / Surgenor, A. / Harris, W. / Smith, I. / Orchard, S. / Flotow, H. / Murray, E.
Citation
Journal: To be Published
Title: Structure of human LCK kinase with a small molecule inhibitor
Authors: Graves, B.J. / Surgenor, A. / Harris, W. / Smith, I. / Orchard, S. / Flotow, H. / Murray, E.
#1: Journal: Nature / Year: 1996
Title: Structural Basis for Activation of Human Lymphocyte Kinase Lck Upon Tyrosine Phosphorylation
Authors: Yamaguchi, H. / Hendrickson, W.A.
History
DepositionNov 10, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 8, 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 13, 2021Group: Database references / Derived calculations
Category: database_2 / struct_conn ...database_2 / struct_conn / 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_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Sep 6, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.5Nov 22, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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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)34,1353
Polymers33,5231
Non-polymers6112
Water2,072115
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.579, 74.160, 92.850
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 Proto-oncogene tyrosine-protein kinase LCK / Lymphocyte cell-specific protein-tyrosine kinase / p56-LCK / LSK / T cell-specific protein-tyrosine kinase


Mass: 33523.137 Da / Num. of mol.: 1 / Fragment: PROTEIN TYROSINE KINASE DOMAIN (RESIDUES 229-509) / Mutation: Y505F
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LCK / Plasmid: PACUW51 / Cell line (production host): SF9 / Cellular location (production host): CYTOPLASM / Gene (production host): POLYHEDRIN / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF9
References: UniProt: P06239, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-LHL / 3-(2,6-dichlorophenyl)-7-({4-[2-(diethylamino)ethoxy]phenyl}amino)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one


Mass: 515.435 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H28Cl2N6O2
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 115 / 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: 2.33 Å3/Da / Density % sol: 47.26 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 1.8-2.5M AMMONIUM SULFATE, 0.1M BISTRIS, PH6.5,VAPOR DIFFUSION, SITTING DROP, 277 DEG K, PROTEIN STOCK AT 1.5 MG/ML

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Data collection

DiffractionMean temperature: 277 K
Diffraction sourceSource: ROTATING ANODE / Type: Cu FINE FOCUS / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: May 1, 1998
RadiationMonochromator: YALE MIRRORS / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.8→30 Å / Num. all: 7251 / Num. obs: 7251 / % possible obs: 94.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3 % / Biso Wilson estimate: 16 Å2 / Rmerge(I) obs: 0.111 / Rsym value: 0.111 / Net I/σ(I): 10.4
Reflection shellResolution: 2.8→2.9 Å / Rmerge(I) obs: 0.261 / Mean I/σ(I) obs: 3.7 / Rsym value: 0.261 / % possible all: 95.7

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Processing

Software
NameVersionClassification
AMoREphasing
CNX2005refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3LCK

3lck


Resolution: 2.8→28.56 Å / Rfactor Rfree error: 0.012 / Data cutoff high absF: 1302833.1 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
Details: RESOLUTION-DEPENDENT WEIGHTING SCHEME OTHER REFINEMENT REMARKS: BULK SOLVENT MODEL USED RESIDUES AT THE N-TERMINUS (MET 222 THROUGH GLN 230), C-TERMINUS (GLU 502 THROUGH PRO 509) AND TWO IN ...Details: RESOLUTION-DEPENDENT WEIGHTING SCHEME OTHER REFINEMENT REMARKS: BULK SOLVENT MODEL USED RESIDUES AT THE N-TERMINUS (MET 222 THROUGH GLN 230), C-TERMINUS (GLU 502 THROUGH PRO 509) AND TWO IN THE ACTIVATION LOOP (GLY 399 AND ALA 400) HAVE WEAK OR NON-EXISTENT ELECTRON DENSITY. THE RESIDUES AT THE TERMINI ARE NOT INCLUDED IN REFINEMENT. THE FOLLOWING RESIDUES HAVE SIDE CHAIN ATOMS WHICH ARE POORLY DEFINED BY ELECTRON DENSITY BUT THEY HAVE BEEN INCLUDED IN REFINEMENT: GLU 237 (ENTIRE SIDE CHAIN), LYS 246 (BEYOND CG), LYS 276 (BEYOND CD), GLN 309 (BEYOND CB), GLU 390 (ENTIRE SIDE CHAIN), ASN 392 (BEYOND CB), ARG 397 (ENTIRE SIDE CHAIN), GLU 398 (BEYOND CB), LYS 401 (BEYOND CB), ARG 438 (BEYOND CD) AND ASN 464 (ENTIRE SIDE CHAIN).
RfactorNum. reflection% reflectionSelection details
Rfree0.223 337 4.6 %RANDOM
Rwork0.165 ---
obs0.167 7251 94.6 %-
all-7251 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 30.66 Å2 / ksol: 0.33 e/Å3
Displacement parametersBiso mean: 19.2 Å2
Baniso -1Baniso -2Baniso -3
1--6.95 Å20 Å20 Å2
2---0.28 Å20 Å2
3---7.23 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.35 Å0.24 Å
Luzzati d res low-5 Å
Luzzati sigma a0.44 Å0.21 Å
Refinement stepCycle: LAST / Resolution: 2.8→28.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2209 0 40 115 2364
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d20.4
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.66
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.361.5
X-RAY DIFFRACTIONc_mcangle_it2.362
X-RAY DIFFRACTIONc_scbond_it2.032
X-RAY DIFFRACTIONc_scangle_it3.162.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 2.8→2.98 Å / Rfactor Rfree error: 0.046 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.333 53 4.4 %
Rwork0.206 1144 -
obs--95.9 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARWATER.TOP
X-RAY DIFFRACTION3ION.PARAMION.TOP
X-RAY DIFFRACTION4RO32-8464.PRXRO32-8464.TPX

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