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- PDB-5xy1: Crystal structure of Lyn kinase domain in complex with N-(1H-inda... -

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Basic information

Entry
Database: PDB / ID: 5xy1
TitleCrystal structure of Lyn kinase domain in complex with N-(1H-indazol-6-yl)-8-(piperidin-4-yloxy)-6-propylquinazolin-2-amine
ComponentsTyrosine-protein kinase Lyn
KeywordsTRANSFERASE / kinase
Function / homology
Function and homology information


C-X-C chemokine receptor CXCR4 signaling pathway / regulation of monocyte chemotaxis / negative regulation of intracellular signal transduction / Fc receptor mediated stimulatory signaling pathway / response to sterol depletion / regulation of mast cell activation / positive regulation of stress-activated protein kinase signaling cascade / negative regulation of myeloid leukocyte differentiation / eosinophil differentiation / positive regulation of Fc receptor mediated stimulatory signaling pathway ...C-X-C chemokine receptor CXCR4 signaling pathway / regulation of monocyte chemotaxis / negative regulation of intracellular signal transduction / Fc receptor mediated stimulatory signaling pathway / response to sterol depletion / regulation of mast cell activation / positive regulation of stress-activated protein kinase signaling cascade / negative regulation of myeloid leukocyte differentiation / eosinophil differentiation / positive regulation of Fc receptor mediated stimulatory signaling pathway / positive regulation of dendritic cell apoptotic process / positive regulation of oligodendrocyte progenitor proliferation / Fc receptor mediated inhibitory signaling pathway / regulation of B cell receptor signaling pathway / integrin alpha2-beta1 complex / tolerance induction to self antigen / negative regulation of toll-like receptor 2 signaling pathway / immune response-regulating cell surface receptor signaling pathway / positive regulation of mast cell proliferation / negative regulation of mast cell proliferation / positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process / glycosphingolipid binding / phosphorylation-dependent protein binding / negative regulation of toll-like receptor 4 signaling pathway / platelet degranulation / regulation of mast cell degranulation / dendritic cell differentiation / : / regulation of platelet aggregation / regulation of B cell apoptotic process / phosphatidylinositol 3-kinase activator activity / oligodendrocyte development / Signaling by Erythropoietin / histamine secretion by mast cell / Platelet Adhesion to exposed collagen / Erythropoietin activates STAT5 / Erythropoietin activates Phospholipase C gamma (PLCG) / interleukin-5-mediated signaling pathway / CD28 co-stimulation / negative regulation of immune response / regulation of release of sequestered calcium ion into cytosol / CD22 mediated BCR regulation / gamma-tubulin binding / platelet-derived growth factor receptor binding / response to carbohydrate / Fc epsilon receptor (FCERI) signaling / EPH-Ephrin signaling / toll-like receptor 4 signaling pathway / Regulation of KIT signaling / postsynaptic specialization, intracellular component / CTLA4 inhibitory signaling / leukocyte migration / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / Fc-gamma receptor signaling pathway involved in phagocytosis / EPHA-mediated growth cone collapse / Dectin-2 family / negative regulation of B cell proliferation / mitochondrial crista / Fc-epsilon receptor signaling pathway / stimulatory C-type lectin receptor signaling pathway / PECAM1 interactions / regulation of cell adhesion mediated by integrin / B cell homeostasis / FCGR activation / EPH-ephrin mediated repulsion of cells / response to axon injury / ephrin receptor signaling pathway / Role of LAT2/NTAL/LAB on calcium mobilization / response to amino acid / growth hormone receptor signaling pathway via JAK-STAT / hematopoietic progenitor cell differentiation / Erythropoietin activates RAS / Growth hormone receptor signaling / cellular response to retinoic acid / Signaling by CSF3 (G-CSF) / positive regulation of glial cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / lipopolysaccharide-mediated signaling pathway / negative regulation of inflammatory response to antigenic stimulus / extrinsic component of cytoplasmic side of plasma membrane / regulation of cytokine production / GPVI-mediated activation cascade / EPHB-mediated forward signaling / T cell costimulation / CD209 (DC-SIGN) signaling / ephrin receptor binding / FCERI mediated Ca+2 mobilization / erythrocyte differentiation / FCGR3A-mediated IL10 synthesis / regulation of ERK1 and ERK2 cascade / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / negative regulation of protein phosphorylation / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / negative regulation of MAP kinase activity / response to hormone / Regulation of signaling by CBL / Cell surface interactions at the vascular wall / FCERI mediated MAPK activation / phosphoprotein binding / FCGR3A-mediated phagocytosis
Similarity search - Function
Tyrosine-protein kinase Lyn, SH3 domain / Tyrosine-protein kinase Lyn, 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 ...Tyrosine-protein kinase Lyn, SH3 domain / Tyrosine-protein kinase Lyn, 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-8H0 / Tyrosine-protein kinase Lyn
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsKim, H.T.
CitationJournal: To Be Published
Title: Crystal structure of Lyn kinase domain in complex with N-(1H-indazol-6-yl)-8-(piperidin-4-yloxy)-6-propylquinazolin-2-amine
Authors: Kim, H.T.
History
DepositionJul 5, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 2, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase Lyn
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2002
Polymers31,7981
Non-polymers4021
Water724
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12400 Å2
Unit cell
Length a, b, c (Å)128.864, 128.864, 55.123
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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Components

#1: Protein Tyrosine-protein kinase Lyn / Lck/Yes-related novel protein tyrosine kinase / V-yes-1 Yamaguchi sarcoma viral related oncogene ...Lck/Yes-related novel protein tyrosine kinase / V-yes-1 Yamaguchi sarcoma viral related oncogene homolog / p53Lyn / p56Lyn


Mass: 31797.541 Da / Num. of mol.: 1 / Fragment: UNP residues 239-512
Source method: isolated from a genetically manipulated source
Details: N-(1H-indazol-6-yl)-8-(piperidin-4-yloxy)-6-propylquinazolin-2-amine
Source: (gene. exp.) Homo sapiens (human) / Gene: LYN, JTK8
Production host: Insect cell expression vector pTIE1 (others)
References: UniProt: P07948, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-8H0 / N-(1H-indazol-6-yl)-8-piperidin-4-yloxy-6-propyl-quinazolin-2-amine


Mass: 402.492 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H26N6O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 4 / 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: 2.77 Å3/Da / Density % sol: 55.6 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 23% PEG3350, 0.1M NaCl and 0.1M HEPES pH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: PAL/PLS / Beamline: 5C (4A) / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210r / Detector: CCD / Date: Jul 3, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. obs: 8833 / % possible obs: 98.99 % / Redundancy: 4.1 % / Rmerge(I) obs: 0.074 / Rsym value: 0.057 / Net I/σ(I): 18.6
Reflection shellResolution: 2.7→2.75 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.381 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 562 / Rsym value: 0.476 / Χ2: 0.886 / % possible all: 97.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3A4O

3a4o


Resolution: 2.7→50 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.909 / SU B: 15.599 / SU ML: 0.304 / Cross valid method: THROUGHOUT / ESU R: 1.139 / ESU R Free: 0.347 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26011 446 4.8 %RANDOM
Rwork0.21366 ---
obs0.21581 8833 98.99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 70.837 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å2-0 Å2
2--0 Å2-0 Å2
3----0.01 Å2
Refinement stepCycle: 1 / Resolution: 2.7→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2036 0 30 4 2070
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.022116
X-RAY DIFFRACTIONr_bond_other_d0.0010.022040
X-RAY DIFFRACTIONr_angle_refined_deg0.9471.9882860
X-RAY DIFFRACTIONr_angle_other_deg0.6834702
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5355251
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.43623.77890
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.55415378
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.3031512
X-RAY DIFFRACTIONr_chiral_restr0.0540.2310
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0212314
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02473
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.197.011010
X-RAY DIFFRACTIONr_mcbond_other2.1917.0071009
X-RAY DIFFRACTIONr_mcangle_it3.70610.5021259
X-RAY DIFFRACTIONr_mcangle_other3.70510.5071260
X-RAY DIFFRACTIONr_scbond_it1.9097.2441106
X-RAY DIFFRACTIONr_scbond_other1.9087.2451107
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.33510.7811602
X-RAY DIFFRACTIONr_long_range_B_refined5.46156.1552500
X-RAY DIFFRACTIONr_long_range_B_other5.46156.1642501
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.701→2.771 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.305 35 -
Rwork0.316 641 -
obs--97.55 %

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