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- PDB-6hvf: Kinase domain of cSrc in complex with compound 29B -

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Basic information

Entry
Database: PDB / ID: 6hvf
TitleKinase domain of cSrc in complex with compound 29B
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsTRANSFERASE / Kinase inhibitor / covalent inhibitor
Function / homology
Function and homology information


Signaling by ERBB2 / Nuclear signaling by ERBB4 / 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 ...Signaling by ERBB2 / Nuclear signaling by ERBB4 / 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 / RET signaling / Receptor Mediated Mitophagy / ADP signalling through P2Y purinoceptor 1 / RAF activation / PIP3 activates AKT signaling / EPH-ephrin mediated repulsion of cells / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Activated NTRK3 signals through PI3K / Downstream signal transduction / Downregulation of ERBB4 signaling / Cyclin D associated events in G1 / Regulation of RUNX3 expression and activity / 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 / negative regulation of intrinsic apoptotic signaling pathway / progesterone receptor signaling pathway / negative regulation of extrinsic apoptotic signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / epidermal growth factor receptor signaling pathway / cell junction / protein tyrosine kinase activity / protein phosphatase binding / mitochondrial inner membrane / cell differentiation / cytoskeleton / regulation of cell cycle / cell adhesion / endosome membrane / innate immune response / signaling receptor binding / focal adhesion / 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-GUT / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesGallus gallus (chicken)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.1 Å
AuthorsKeul, M. / Mueller, M.P. / Rauh, D.
Funding support Germany, 2items
OrganizationGrant numberCountry
German Federal Ministry for Education and Research01GS08104 Germany
German Federal Ministry for Education and Research01ZX1303C Germany
CitationJournal: Chem Sci / Year: 2019
Title: Inhibition of osimertinib-resistant epidermal growth factor receptor EGFR-T790M/C797S.
Authors: Lategahn, J. / Keul, M. / Klovekorn, P. / Tumbrink, H.L. / Niggenaber, J. / Muller, M.P. / Hodson, L. / Flasshoff, M. / Hardick, J. / Grabe, T. / Engel, J. / Schultz-Fademrecht, C. / ...Authors: Lategahn, J. / Keul, M. / Klovekorn, P. / Tumbrink, H.L. / Niggenaber, J. / Muller, M.P. / Hodson, L. / Flasshoff, M. / Hardick, J. / Grabe, T. / Engel, J. / Schultz-Fademrecht, C. / Baumann, M. / Ketzer, J. / Muhlenberg, T. / Hiller, W. / Gunther, G. / Unger, A. / Muller, H. / Heimsoeth, A. / Golz, C. / Blank-Landeshammer, B. / Kollipara, L. / Zahedi, R.P. / Strohmann, C. / Hengstler, J.G. / van Otterlo, W.A.L. / Bauer, S. / Rauh, D.
History
DepositionOct 10, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 23, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2019Group: Data collection / 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.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Jan 1, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_id_ISSN / _citation.journal_volume ..._citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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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
B: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,6977
Polymers65,5462
Non-polymers1,1515
Water3,117173
1
A: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3804
Polymers32,7731
Non-polymers6073
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)33,3173
Polymers32,7731
Non-polymers5452
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.170, 62.970, 74.540
Angle α, β, γ (deg.)100.23, 91.64, 90.03
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: 32772.801 Da / Num. of mol.: 2 / Mutation: T338M, S345C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Gallus gallus (chicken) / Gene: SRC / Production host: Escherichia coli BL21 (bacteria)
References: UniProt: P00523, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-GUT / ~{N}-[3-[3-ethyl-6-[4-(4-methylpiperazin-1-yl)phenyl]-4-oxidanylidene-7~{H}-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl]prop-2-enamide


Mass: 482.577 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H30N6O2
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 173 / 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: 2.97 Å3/Da / Density % sol: 58.59 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 10% ethylene glycol, 10 mM sodium chloride, pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.97856 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Oct 26, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 42945 / % possible obs: 97.5 % / Redundancy: 3.5 % / Net I/σ(I): 8.37
Reflection shellResolution: 2.1→2.2 Å

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Processing

Software
NameVersionClassification
PHENIX(1.10_2155: ???)refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementResolution: 2.1→43.657 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.98 / Phase error: 26.5
RfactorNum. reflection% reflection
Rfree0.2451 2147 5 %
Rwork0.2107 --
obs0.2124 42926 97.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.1→43.657 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3865 0 84 173 4122
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0044087
X-RAY DIFFRACTIONf_angle_d0.6845551
X-RAY DIFFRACTIONf_dihedral_angle_d13.9732491
X-RAY DIFFRACTIONf_chiral_restr0.044596
X-RAY DIFFRACTIONf_plane_restr0.004707
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.14880.33761400.29652641X-RAY DIFFRACTION96
2.1488-2.20260.31881440.26312737X-RAY DIFFRACTION97
2.2026-2.26210.29631420.25022701X-RAY DIFFRACTION97
2.2621-2.32870.28451450.24562750X-RAY DIFFRACTION97
2.3287-2.40390.24781420.2312695X-RAY DIFFRACTION97
2.4039-2.48980.26891420.22412708X-RAY DIFFRACTION97
2.4898-2.58940.28091420.20932688X-RAY DIFFRACTION97
2.5894-2.70730.26151430.21342738X-RAY DIFFRACTION98
2.7073-2.850.25451440.20672729X-RAY DIFFRACTION98
2.85-3.02850.24731440.20362747X-RAY DIFFRACTION98
3.0285-3.26230.24451430.21662719X-RAY DIFFRACTION98
3.2623-3.59040.21681430.19252706X-RAY DIFFRACTION98
3.5904-4.10960.23961430.19062729X-RAY DIFFRACTION98
4.1096-5.17640.22731440.19252736X-RAY DIFFRACTION98
5.1764-43.66620.21911460.21992755X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.86360.1445-0.03182.44280.56141.4921-0.02670.41-0.0097-0.39590.0262-0.0077-0.07440.07210.00530.2736-0.0030.02220.22870.00320.3296-1.348629.65533.3239
22.4644-0.1906-0.04242.4809-0.30911.8448-0.0712-0.3020.1370.46420.05980.0326-0.083-0.00180.01570.30530.01430.01990.2036-0.00050.3423-8.7885-1.600822.3117
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resseq 257:533)
2X-RAY DIFFRACTION2(chain B and resseq 258:533)

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