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- PDB-4u5j: C-Src in complex with Ruxolitinib -

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Basic information

Entry
Database: PDB / ID: 4u5j
TitleC-Src in complex with Ruxolitinib
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / c-Src / Ruxolitinib / kinase / inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


Signaling by ERBB2 / Nuclear signaling by ERBB4 / PIP3 activates AKT signaling / Signaling by SCF-KIT / Regulation of KIT signaling / Signaling by EGFR / GAB1 signalosome / Regulation of gap junction activity / FCGR activation / PECAM1 interactions ...Signaling by ERBB2 / Nuclear signaling by ERBB4 / PIP3 activates AKT signaling / Signaling by SCF-KIT / Regulation of KIT signaling / Signaling by EGFR / GAB1 signalosome / Regulation of gap junction activity / FCGR activation / PECAM1 interactions / CD28 co-stimulation / CTLA4 inhibitory signaling / EPHA-mediated growth cone collapse / Ephrin signaling / G alpha (i) signalling events / GP1b-IX-V activation signalling / Thrombin signalling through proteinase activated receptors (PARs) / VEGFR2 mediated cell proliferation / RAF activation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RET signaling / Receptor Mediated Mitophagy / ADP signalling through P2Y purinoceptor 1 / Downregulation of ERBB4 signaling / EPH-ephrin mediated repulsion of cells / Cyclin D associated events in G1 / Regulation of RUNX3 expression and activity / Activated NTRK3 signals through PI3K / Downstream signal transduction / MAP2K and MAPK activation / Integrin signaling / GRB2:SOS provides linkage to MAPK signaling for Integrins / DCC mediated attractive signaling / MET activates PTK2 signaling / Extra-nuclear estrogen signaling / EPHB-mediated forward signaling / p130Cas linkage to MAPK signaling for integrins / VEGFA-VEGFR2 Pathway / connexin binding / progesterone receptor signaling pathway / negative regulation of intrinsic apoptotic signaling pathway / epidermal growth factor receptor signaling pathway / negative regulation of extrinsic apoptotic signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / cell junction / protein phosphatase binding / protein tyrosine kinase activity / cell differentiation / endosome membrane / cytoskeleton / regulation of cell cycle / cell adhesion / mitochondrial inner membrane / innate immune response / focal adhesion / signaling receptor binding / heme binding / perinuclear region of cytoplasm / protein-containing complex / ATP binding / membrane / nucleus / plasma membrane / cytosol
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 / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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-RXT / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesGallus gallus (chicken)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.26 Å
AuthorsChen, Y. / Duan, Y. / Chen, L.
Funding support China, United States, 3items
OrganizationGrant numberCountry
National Natural Science Foundation of China81272971 China
National Natural Science Foundation of China81372904 China
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)5R01GM064642 United States
CitationJournal: Plos One / Year: 2014
Title: c-Src Binds to the Cancer Drug Ruxolitinib with an Active Conformation
Authors: Duan, Y. / Chen, L. / Chen, Y. / Fan, X.G.
History
DepositionJul 25, 2014Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Sep 17, 2014Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2017Group: Advisory / Author supporting evidence ...Advisory / Author supporting evidence / Derived calculations / Other / Source and taxonomy / Structure summary
Category: entity_src_gen / pdbx_audit_support ...entity_src_gen / pdbx_audit_support / pdbx_database_status / pdbx_struct_assembly / pdbx_struct_oper_list / pdbx_validate_symm_contact / struct_keywords
Item: _entity_src_gen.pdbx_alt_source_flag / _pdbx_audit_support.funding_organization ..._entity_src_gen.pdbx_alt_source_flag / _pdbx_audit_support.funding_organization / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_oper_list.symmetry_operation / _pdbx_validate_symm_contact.auth_asym_id_1 / _pdbx_validate_symm_contact.auth_atom_id_1 / _pdbx_validate_symm_contact.auth_atom_id_2 / _pdbx_validate_symm_contact.auth_comp_id_1 / _pdbx_validate_symm_contact.auth_comp_id_2 / _pdbx_validate_symm_contact.auth_seq_id_1 / _pdbx_validate_symm_contact.auth_seq_id_2 / _pdbx_validate_symm_contact.dist / _pdbx_validate_symm_contact.site_symmetry_2 / _struct_keywords.text
Revision 1.2Mar 23, 2022Group: Author supporting evidence / Database references / Refinement description
Category: database_2 / pdbx_audit_support / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_audit_support.funding_organization
Revision 1.3Jun 26, 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: Proto-oncogene tyrosine-protein kinase Src
B: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,0664
Polymers65,4532
Non-polymers6132
Water3,243180
1
A: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,0332
Polymers32,7271
Non-polymers3061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,0332
Polymers32,7271
Non-polymers3061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.107, 63.228, 73.989
Angle α, β, γ (deg.)79.27, 89.27, 90.29
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 32726.645 Da / Num. of mol.: 2 / Fragment: UNP residues 251-533
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Gallus gallus (chicken) / Gene: SRC / Production host: Escherichia coli #1/H766 (bacteria)
References: UniProt: P00523, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-RXT / (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile / Ruxolitinib


Mass: 306.365 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H18N6 / Comment: medication, inhibitor*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 180 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.96 Å3/Da / Density % sol: 58.4 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / Details: PEG 4000

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.987 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 28, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.26→50 Å / Num. obs: 34648 / % possible obs: 97.3 % / Redundancy: 3.5 % / Net I/σ(I): 15.9

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Processing

SoftwareName: PHENIX / Version: (phenix.refine: 1.8.4_1496) / Classification: refinement
RefinementResolution: 2.26→43.398 Å / SU ML: 0.31 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 27.63 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2358 1786 5.25 %
Rwork0.1971 --
obs0.1992 34000 96.79 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.26→43.398 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4290 0 46 180 4516
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0094446
X-RAY DIFFRACTIONf_angle_d1.2736022
X-RAY DIFFRACTIONf_dihedral_angle_d17.4321674
X-RAY DIFFRACTIONf_chiral_restr0.049644
X-RAY DIFFRACTIONf_plane_restr0.007768
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.26-2.32110.37021260.33232289X-RAY DIFFRACTION88
2.3211-2.38940.30431360.28132446X-RAY DIFFRACTION96
2.3894-2.46650.28561430.25282502X-RAY DIFFRACTION97
2.4665-2.55470.32121370.25762423X-RAY DIFFRACTION96
2.5547-2.65690.27021350.22972520X-RAY DIFFRACTION98
2.6569-2.77780.28631410.21712490X-RAY DIFFRACTION98
2.7778-2.92430.24751380.21252510X-RAY DIFFRACTION98
2.9243-3.10740.28251330.2112505X-RAY DIFFRACTION98
3.1074-3.34730.2591420.20322515X-RAY DIFFRACTION98
3.3473-3.6840.2331300.18072523X-RAY DIFFRACTION98
3.684-4.21670.1861480.17112535X-RAY DIFFRACTION98
4.2167-5.3110.19581400.16182475X-RAY DIFFRACTION98
5.311-43.40610.18761370.16322481X-RAY DIFFRACTION97

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