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- PDB-6e6e: DGY-06-116, a novel and selective covalent inhibitor of SRC kinase -

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Basic information

Entry
Database: PDB / ID: 6e6e
TitleDGY-06-116, a novel and selective covalent inhibitor of SRC kinase
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsTRANSFERASE/TRANSFERASE inhibitor / PROTO-ONCOGENE TYROSINE-PROTEIN KINASE SRC / TRANSFERASE / TRANSFERASE-TRANSFERASE inhibitor complex
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 / entry of bacterium into host cell / positive regulation of protein transport / Regulation of gap junction activity / regulation of vascular permeability / 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 / positive regulation of protein processing / skeletal muscle cell proliferation / negative regulation of telomerase activity / intestinal epithelial cell development / Netrin mediated repulsion signals / regulation of intracellular estrogen receptor signaling pathway / 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 / response to acidic pH / signal complex assembly / podosome / positive regulation of small GTPase mediated signal transduction / positive regulation of Ras protein signal transduction / Regulation of RUNX1 Expression and Activity / regulation of bone resorption / positive regulation of podosome assembly / branching involved in mammary gland duct morphogenesis / DCC mediated attractive signaling / adherens junction organization / EPH-Ephrin signaling / myoblast proliferation / Ephrin signaling / osteoclast development / negative regulation of mitochondrial depolarization / odontogenesis / cellular response to peptide hormone stimulus / Signal regulatory protein family interactions / cellular response to fatty acid / MET activates PTK2 signaling / regulation of early endosome to late endosome transport / oogenesis / Regulation of KIT signaling / postsynaptic specialization, intracellular component / Signaling by ALK / Receptor Mediated Mitophagy / GP1b-IX-V activation signalling / CTLA4 inhibitory signaling / leukocyte migration / phospholipase activator activity / interleukin-6-mediated signaling pathway / DNA biosynthetic process / Fc-gamma receptor signaling pathway involved in phagocytosis / EPHA-mediated growth cone collapse / negative regulation of hippo signaling / p130Cas linkage to MAPK signaling for integrins / positive regulation of epithelial cell migration / positive regulation of Notch signaling pathway / Signaling by EGFR / cellular response to platelet-derived growth factor stimulus / stress fiber assembly / positive regulation of smooth muscle cell migration / regulation of heart rate by cardiac conduction / RUNX2 regulates osteoblast differentiation / Recycling pathway of L1 / dendritic growth cone / progesterone receptor signaling pathway / stimulatory C-type lectin receptor signaling pathway / PECAM1 interactions / uterus development / phospholipase binding / neurotrophin TRK receptor signaling pathway / GRB2:SOS provides linkage to MAPK signaling for Integrins / Long-term potentiation / RHOU GTPase cycle / negative regulation of telomere maintenance via telomerase / platelet-derived growth factor receptor signaling pathway / negative regulation of anoikis / RET signaling / FCGR activation
Similarity search - Function
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 ...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-HVY / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsGurbani, D. / Bera, A. / Westover, K.
CitationJournal: Front Mol Biosci / Year: 2020
Title: Structure and Characterization of a Covalent Inhibitor of Src Kinase.
Authors: Gurbani, D. / Du, G. / Henning, N.J. / Rao, S. / Bera, A.K. / Zhang, T. / Gray, N.S. / Westover, K.D.
History
DepositionJul 24, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 31, 2019Provider: repository / Type: Initial release
Revision 2.0Dec 11, 2019Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Structure summary
Category: atom_site / pdbx_poly_seq_scheme ...atom_site / pdbx_poly_seq_scheme / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_residues / pdbx_validate_torsion / struct_conf / struct_conn / struct_mon_prot_cis / struct_ref_seq / struct_sheet_range / struct_site_gen
Item: _atom_site.auth_seq_id / _pdbx_poly_seq_scheme.pdb_seq_num ..._atom_site.auth_seq_id / _pdbx_poly_seq_scheme.pdb_seq_num / _pdbx_struct_sheet_hbond.range_1_auth_seq_id / _pdbx_struct_sheet_hbond.range_2_auth_seq_id / _pdbx_unobs_or_zero_occ_residues.auth_seq_id / _pdbx_validate_torsion.auth_seq_id / _struct_conf.beg_auth_seq_id / _struct_conf.end_auth_seq_id / _struct_conn.ptnr1_auth_seq_id / _struct_mon_prot_cis.auth_seq_id / _struct_mon_prot_cis.pdbx_auth_seq_id_2 / _struct_ref_seq.pdbx_auth_seq_align_beg / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_sheet_range.beg_auth_seq_id / _struct_sheet_range.end_auth_seq_id / _struct_site_gen.auth_seq_id
Revision 2.1Jun 24, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 2.2Oct 11, 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

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Assembly

Deposited unit
A: Proto-oncogene tyrosine-protein kinase Src
B: Proto-oncogene tyrosine-protein kinase Src
C: Proto-oncogene tyrosine-protein kinase Src
D: Proto-oncogene tyrosine-protein kinase Src
E: Proto-oncogene tyrosine-protein kinase Src
F: Proto-oncogene tyrosine-protein kinase Src
G: Proto-oncogene tyrosine-protein kinase Src
H: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)258,04416
Polymers253,2518
Non-polymers4,7938
Water7,837435
1
A: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2552
Polymers31,6561
Non-polymers5991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2552
Polymers31,6561
Non-polymers5991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2552
Polymers31,6561
Non-polymers5991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2552
Polymers31,6561
Non-polymers5991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
5
E: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2552
Polymers31,6561
Non-polymers5991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
6
F: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2552
Polymers31,6561
Non-polymers5991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
7
G: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2552
Polymers31,6561
Non-polymers5991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
8
H: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2552
Polymers31,6561
Non-polymers5991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)63.534, 84.028, 120.109
Angle α, β, γ (deg.)89.962, 90.046, 90.118
Int Tables number1
Space group name H-MP1
Space group name HallP1

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Components

#1: Protein
Proto-oncogene tyrosine-protein kinase Src / / Proto-oncogene c-Src / pp60c-src / p60-Src


Mass: 31656.355 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SRC, SRC1 / Production host: Escherichia coli (E. coli)
References: UniProt: P12931, non-specific protein-tyrosine kinase
#2: Chemical
ChemComp-HVY / N-(2-chloro-6-methylphenyl)-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4-{[2-(propanoylamino)phenyl]amino}pyrimidine-5-carboxamide


Mass: 599.126 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C32H35ClN8O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 435 / 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: 2.53 Å3/Da / Density % sol: 51.44 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 0.1M Magnesium Formate Dihydrate; 15% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97951 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jun 14, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97951 Å / Relative weight: 1
ReflectionResolution: 2.15→50 Å / Num. obs: 123213 / % possible obs: 91.7 % / Redundancy: 3.6 % / Biso Wilson estimate: 36.4 Å2 / Rmerge(I) obs: 0.127 / Rpim(I) all: 0.076 / Net I/σ(I): 9.68
Reflection shellResolution: 2.15→2.19 Å / Redundancy: 3 % / Rmerge(I) obs: 0.964 / Num. unique obs: 6186 / % possible all: 91.6

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Processing

Software
NameVersionClassification
PHENIX1.14rc3_3199refinement
PDB_EXTRACT3.24data extraction
HKL-3000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4MXO

4mxo


Resolution: 2.15→43.66 Å / SU ML: 0.34 / Cross valid method: THROUGHOUT / σ(F): 1.96 / Phase error: 36.3411
RfactorNum. reflection% reflection
Rfree0.2849 5955 4.86 %
Rwork0.2499 --
obs0.2517 122649 90.78 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 46.64 Å2
Refinement stepCycle: LAST / Resolution: 2.15→43.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms17436 0 0 435 17871
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002217948
X-RAY DIFFRACTIONf_angle_d0.592324343
X-RAY DIFFRACTIONf_chiral_restr0.04062571
X-RAY DIFFRACTIONf_plane_restr0.0043112
X-RAY DIFFRACTIONf_dihedral_angle_d14.47510968
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.15-2.170.33521620.333168X-RAY DIFFRACTION75.44
2.17-2.20.40132030.33233953X-RAY DIFFRACTION91.28
2.2-2.230.31281730.32983968X-RAY DIFFRACTION91.9
2.23-2.250.37912080.33173925X-RAY DIFFRACTION91.64
2.25-2.280.35961580.31373958X-RAY DIFFRACTION91.26
2.28-2.320.32461640.31443905X-RAY DIFFRACTION91.62
2.32-2.350.35071970.30224007X-RAY DIFFRACTION90.94
2.35-2.380.39891730.30573802X-RAY DIFFRACTION89.55
2.38-2.420.33941950.29373819X-RAY DIFFRACTION89.16
2.42-2.460.35752060.28223728X-RAY DIFFRACTION86.69
2.46-2.50.36421900.27453400X-RAY DIFFRACTION80.13
2.5-2.550.28951810.26864036X-RAY DIFFRACTION93.34
2.55-2.60.3271800.27764009X-RAY DIFFRACTION94.69
2.6-2.650.34031920.28624146X-RAY DIFFRACTION94.37
2.65-2.710.32232130.26634028X-RAY DIFFRACTION94.12
2.71-2.770.32372550.25143980X-RAY DIFFRACTION93.84
2.77-2.840.32792280.25743927X-RAY DIFFRACTION93.56
2.84-2.920.34492080.26264012X-RAY DIFFRACTION92.81
2.92-30.29132400.26483919X-RAY DIFFRACTION91.77
3-3.10.31441880.26443859X-RAY DIFFRACTION90.74
3.1-3.210.29332180.26083626X-RAY DIFFRACTION85.59
3.21-3.340.24092040.24843819X-RAY DIFFRACTION88.83
3.34-3.490.27522240.23594086X-RAY DIFFRACTION95.65
3.49-3.680.3161890.23174083X-RAY DIFFRACTION95.59
3.68-3.910.24271960.23434128X-RAY DIFFRACTION95.03
3.91-4.210.26342270.21724015X-RAY DIFFRACTION93.77
4.21-4.630.19971560.20543856X-RAY DIFFRACTION90.24
4.63-5.30.26131720.20853942X-RAY DIFFRACTION90.38
5.3-6.670.28142650.24254035X-RAY DIFFRACTION96.22
6.67-43.670.21171900.22713555X-RAY DIFFRACTION83.24

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