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- PDB-2h8h: Src kinase in complex with a quinazoline inhibitor -

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Basic information

Entry
Database: PDB / ID: 2h8h
TitleSrc kinase in complex with a quinazoline inhibitor
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsTRANSFERASE / SRC KINASE
Function / homology
Function and homology information


regulation of toll-like receptor 3 signaling pathway / positive regulation of non-membrane spanning protein tyrosine kinase activity / primary ovarian follicle growth / regulation of caveolin-mediated endocytosis / positive regulation of ovarian follicle development / cellular response to prolactin / positive regulation of platelet-derived growth factor receptor-beta signaling pathway / positive regulation of male germ cell proliferation / dendritic filopodium / regulation of cell projection assembly ...regulation of toll-like receptor 3 signaling pathway / positive regulation of non-membrane spanning protein tyrosine kinase activity / primary ovarian follicle growth / regulation of caveolin-mediated endocytosis / positive regulation of ovarian follicle development / cellular response to prolactin / positive regulation of platelet-derived growth factor receptor-beta signaling pathway / positive regulation of male germ cell proliferation / dendritic filopodium / regulation of cell projection assembly / regulation of cell-cell adhesion / positive regulation of dephosphorylation / response to mineralocorticoid / Regulation of commissural axon pathfinding by SLIT and ROBO / ERBB2 signaling pathway / regulation of epithelial cell migration / positive regulation of protein transport / Regulation of gap junction activity / regulation of vascular permeability / entry of bacterium into host cell / BMP receptor binding / positive regulation of lamellipodium morphogenesis / cellular response to progesterone stimulus / positive regulation of integrin activation / Activated NTRK2 signals through FYN / negative regulation of focal adhesion assembly / skeletal muscle cell proliferation / positive regulation of protein processing / Netrin mediated repulsion signals / regulation of intracellular estrogen receptor signaling pathway / intestinal epithelial cell development / CD28 co-stimulation / positive regulation of glucose metabolic process / transcytosis / Activated NTRK3 signals through PI3K / connexin binding / cellular response to fluid shear stress / focal adhesion assembly / signal complex assembly / response to acidic pH / podosome / negative regulation of telomere maintenance via telomerase / positive regulation of small GTPase mediated signal transduction / positive regulation of Ras protein signal transduction / positive regulation of podosome assembly / Regulation of RUNX1 Expression and Activity / regulation of bone resorption / branching involved in mammary gland duct morphogenesis / DCC mediated attractive signaling / negative regulation of mitochondrial depolarization / adherens junction organization / osteoclast development / myoblast proliferation / EPH-Ephrin signaling / Ephrin signaling / odontogenesis / cellular response to peptide hormone stimulus / Signal regulatory protein family interactions / cellular response to fatty acid / regulation of early endosome to late endosome transport / MET activates PTK2 signaling / oogenesis / Receptor Mediated Mitophagy / GP1b-IX-V activation signalling / Regulation of KIT signaling / Signaling by ALK / postsynaptic specialization, intracellular component / CTLA4 inhibitory signaling / Signaling by EGFR / phospholipase activator activity / leukocyte migration / DNA biosynthetic process / EPHA-mediated growth cone collapse / Fc-gamma receptor signaling pathway involved in phagocytosis / interleukin-6-mediated signaling pathway / p130Cas linkage to MAPK signaling for integrins / negative regulation of hippo signaling / positive regulation of epithelial cell migration / positive regulation of Notch signaling pathway / stress fiber assembly / negative regulation of telomerase activity / cellular response to platelet-derived growth factor stimulus / positive regulation of smooth muscle cell migration / regulation of heart rate by cardiac conduction / Recycling pathway of L1 / RUNX2 regulates osteoblast differentiation / progesterone receptor signaling pathway / dendritic growth cone / stimulatory C-type lectin receptor signaling pathway / uterus development / PECAM1 interactions / phospholipase binding / neurotrophin TRK receptor signaling pathway / Long-term potentiation / GRB2:SOS provides linkage to MAPK signaling for Integrins / RHOU GTPase cycle / platelet-derived growth factor receptor signaling pathway / FCGR activation / EPH-ephrin mediated repulsion of cells / negative regulation of anoikis
Similarity search - Function
SH2 domain / SHC Adaptor Protein / SH3 Domains / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH3 type barrels. ...SH2 domain / SHC Adaptor Protein / SH3 Domains / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH3 type barrels. / 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 / Roll / 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 Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-H8H / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsOtterbein, L.R. / Norman, R. / Pauptit, R.A. / Rowsell, S. / Breed, J.
CitationJournal: J.Med.Chem. / Year: 2006
Title: N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor.
Authors: Hennequin, L.F. / Allen, J. / Breed, J. / Curwen, J. / Fennell, M. / Green, T.P. / Lambert-van der Brempt, C. / Morgentin, R. / Norman, R.A. / Olivier, A. / Otterbein, L. / Ple, P.A. / Warin, N. / Costello, G.
History
DepositionJun 7, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 21, 2006Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2007Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Advisory / Derived calculations / Version format compliance
Revision 1.3Jul 1, 2015Group: Non-polymer description
Revision 1.4Apr 3, 2024Group: 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_conn / 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_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 Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,3972
Polymers59,8551
Non-polymers5421
Water3,981221
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)49.806, 72.467, 171.566
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 Src / / p60-Src / c- Src / pp60c-src


Mass: 59855.359 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SRC, SRC1 / Cell line (production host): SF9 cells / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P12931, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-H8H / N-(5-CHLORO-1,3-BENZODIOXOL-4-YL)-7-[2-(4-METHYLPIPERAZIN-1-YL)ETHOXY]-5-(TETRAHYDRO-2H-PYRAN-4-YLOXY)QUINAZOLIN-4-AMINE / SARACATINIB / Saracatinib


Mass: 542.026 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H32ClN5O5 / Comment: inhibitor*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 221 / 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: 2.584947 Å3/Da / Density % sol: 52.416824 %
Crystal growTemperature: 288 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 50 mM PIPES pH 6.5, 10 mM DTT, 100 mM sodium chloride and 4 to 9% PEG4000 (w/v), VAPOR DIFFUSION, SITTING DROP, temperature 288K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 1.5418 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Nov 27, 2003 / Details: toroidal focusing mirror
RadiationMonochromator: double crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→49.8 Å / Num. obs: 29365 / % possible obs: 95.49 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 3.4 % / Rmerge(I) obs: 0.083 / Rsym value: 0.115
Reflection shellResolution: 2.2→2.32 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.586 / Num. unique all: 4508 / Rsym value: 0.788 / % possible all: 97.2

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
ADSCdata collection
MOSFLMdata reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: In House

Resolution: 2.2→47.67 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.904 / SU B: 15.374 / SU ML: 0.169 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 1 / ESU R: 0.245 / ESU R Free: 0.225 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27216 1566 5.1 %RANDOM
Rwork0.20351 ---
obs0.20686 29365 95.49 %-
all-29365 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 34.121 Å2
Baniso -1Baniso -2Baniso -3
1-1.79 Å20 Å20 Å2
2--0.46 Å20 Å2
3----2.25 Å2
Refinement stepCycle: LAST / Resolution: 2.2→47.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3581 0 38 221 3840
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0223735
X-RAY DIFFRACTIONr_bond_other_d0.0010.023297
X-RAY DIFFRACTIONr_angle_refined_deg1.4441.9785067
X-RAY DIFFRACTIONr_angle_other_deg1.02637685
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8975448
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.33923.678174
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.13915638
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.7771527
X-RAY DIFFRACTIONr_chiral_restr0.0810.2538
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.024125
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02774
X-RAY DIFFRACTIONr_nbd_refined0.2030.2741
X-RAY DIFFRACTIONr_nbd_other0.1860.23233
X-RAY DIFFRACTIONr_nbtor_refined0.1870.21814
X-RAY DIFFRACTIONr_nbtor_other0.0880.22068
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1660.2184
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.0350.21
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0770.213
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2560.251
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1960.218
X-RAY DIFFRACTIONr_mcbond_it0.841.52286
X-RAY DIFFRACTIONr_mcbond_other0.1441.5904
X-RAY DIFFRACTIONr_mcangle_it1.39423600
X-RAY DIFFRACTIONr_scbond_it1.84231694
X-RAY DIFFRACTIONr_scangle_it2.914.51467
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.344 105 -
Rwork0.306 1971 -
obs--87.93 %
Refinement TLS params.Method: refined / Origin x: 19.4577 Å / Origin y: 32.8529 Å / Origin z: 66.721 Å
111213212223313233
T-0.09 Å20.046 Å20.0038 Å2--0.0778 Å20.0137 Å2---0.0451 Å2
L0.6254 °20.4351 °2-0.2318 °2-0.998 °2-0.0904 °2--0.764 °2
S-0.0081 Å °0.0127 Å °-0.0033 Å °-0.036 Å °0.0002 Å °-0.006 Å °-0.101 Å °-0.0488 Å °0.0079 Å °

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