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- PDB-7ah3: Kinase domain of cSrc in complex with a pyrazolopyrimidine -

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Basic information

Entry
Database: PDB / ID: 7ah3
TitleKinase domain of cSrc in complex with a pyrazolopyrimidine
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsONCOPROTEIN / Kinase domain substituted pyrazolopyrimidine Inhibitor complex c-Src inhibitor
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 / osteoclast development / progesterone receptor signaling pathway / negative regulation of intrinsic apoptotic signaling pathway / bone resorption / extrinsic component of cytoplasmic side of plasma membrane / 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 phosphatase binding / protein tyrosine kinase activity / mitochondrial inner membrane / cell differentiation / cytoskeleton / endosome membrane / cell adhesion / regulation of cell cycle / cell cycle / phosphorylation / 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 ...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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-RCK / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesGallus gallus (chicken)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsDello Iacono, L. / Kleinboelting, S. / Fallacara, A.L. / Rauh, D.
Funding support Italy, 1items
OrganizationGrant numberCountry
Italian Association for Cancer ResearchAIRC IG_4538 Italy
CitationJournal: To Be Published
Title: Insights into the binding of pyrazolopyrimidines to Src kinase
Authors: Dello Iacono, L. / Kleinboelting, S. / Passannanti, R. / Fallacara, A.L. / Di Pisa, F. / Richters, A. / Musumeci, F. / Rauh, D. / Schenone, S. / Botta, M.
History
DepositionSep 24, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 6, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)66,92111
Polymers65,4532
Non-polymers1,4689
Water5,963331
1
A: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4075
Polymers32,7271
Non-polymers6814
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)33,5146
Polymers32,7271
Non-polymers7875
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.260, 63.420, 74.930
Angle α, β, γ (deg.)101.722, 90.895, 90.008
Int Tables number1
Space group name H-MP1
Space group name HallP1
Symmetry operation#1: x,y,z

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 32726.645 Da / Num. of mol.: 2
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

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Non-polymers , 5 types, 340 molecules

#2: Chemical ChemComp-RCK / ~{N}-[(2-fluorophenyl)methyl]-6-(morpholin-4-ylmethylsulfanyl)-1-(2-phenylethyl)pyrazolo[3,4-d]pyrimidin-4-amine


Mass: 478.585 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H27FN6OS / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 331 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 3 Å3/Da / Density % sol: 59.05 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 0 to 30 mM NaCl, pH 7.0 9 to 20 % ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Dec 9, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.95→43.26 Å / Num. obs: 53873 / % possible obs: 97 % / Redundancy: 3.5 % / Biso Wilson estimate: 36.02 Å2 / CC1/2: 0.997 / CC star: 0.999 / Rmerge(I) obs: 0.08281 / Rpim(I) all: 0.05208 / Rrim(I) all: 0.09816 / Net I/σ(I): 9.19
Reflection shellResolution: 1.95→2.02 Å / Redundancy: 3.4 % / Rmerge(I) obs: 1.196 / Num. unique obs: 5274 / CC1/2: 0.441 / CC star: 0.782 / Rpim(I) all: 0.7625 / Rrim(I) all: 1.424 / % possible all: 95.13

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4o2p

4o2p


Resolution: 1.95→43.26 Å / SU ML: 0.2547 / Cross valid method: FREE R-VALUE / σ(F): 1.95 / Phase error: 24.4796
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2264 2693 5 %
Rwork0.1872 51163 -
obs0.1891 53856 97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 51.04 Å2
Refinement stepCycle: LAST / Resolution: 1.95→43.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4077 0 100 331 4508
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.014310
X-RAY DIFFRACTIONf_angle_d1.69065849
X-RAY DIFFRACTIONf_chiral_restr0.093628
X-RAY DIFFRACTIONf_plane_restr0.01741
X-RAY DIFFRACTIONf_dihedral_angle_d18.8685612
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-1.990.36161350.32292558X-RAY DIFFRACTION93.64
1.99-2.020.33121430.28932734X-RAY DIFFRACTION96.58
2.02-2.060.29531400.27112659X-RAY DIFFRACTION96.78
2.06-2.110.27061440.26332730X-RAY DIFFRACTION96.9
2.11-2.160.30331390.25642636X-RAY DIFFRACTION96.32
2.16-2.210.26991420.24752701X-RAY DIFFRACTION96.87
2.21-2.270.2781400.25342656X-RAY DIFFRACTION96.15
2.27-2.340.29751430.24292703X-RAY DIFFRACTION96.51
2.34-2.420.28061390.23092655X-RAY DIFFRACTION97.12
2.42-2.50.26631440.20052732X-RAY DIFFRACTION96.9
2.5-2.60.21831410.18852670X-RAY DIFFRACTION97.37
2.6-2.720.22911430.18442727X-RAY DIFFRACTION97.75
2.72-2.860.23551440.18972736X-RAY DIFFRACTION98.43
2.86-3.040.20481440.18562742X-RAY DIFFRACTION98.06
3.04-3.280.22821430.18042705X-RAY DIFFRACTION98.21
3.28-3.610.18721440.16012731X-RAY DIFFRACTION97.89
3.61-4.130.21551420.15532696X-RAY DIFFRACTION97.83
4.13-5.20.1871410.14862684X-RAY DIFFRACTION96.48
5.2-43.260.21321420.18272708X-RAY DIFFRACTION97.27
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)
10.880626382406-0.160027497058-0.1613190271932.835749010781.718924442788.530990151510.074805524997-0.3384151096990.1011271163581.00179391509-0.164092235133-0.01468087216220.131165578265-0.4722097949990.06266433992470.634626566911-0.0673124375909-0.002657775004730.38693840996-0.0452920682860.327655012608-4.852107962384.0497959063835.8293807131
23.1026186434-0.599921549106-0.4711481123883.40117220580.06670473126772.63150748736-0.03239019493570.06654050033840.03136636856080.12594630441-0.07446206185570.237121853991-0.00885803674627-0.4688323915920.09900319805780.232030265872-0.0431132726580.006297866135660.257456153839-0.04144034953030.236636976482-12.9229958473-4.1061906358914.1765785322
34.30695025573-2.9170766299-2.459255377674.972035669291.180124316175.151322206660.6307572231560.3695474688570.635069608691-0.859741927864-0.309906901634-0.123636269198-1.88838906769-0.0257881524175-0.2007416670211.336276248320.053692888628-0.03499680374610.515924845235-0.001543846346620.479505649422-6.42846164622-24.7971620655-17.7894119281
42.1008485568-0.189443283977-1.268384451312.88030899962-0.004280219820785.393789600040.04054155301220.2728233411160.0581549782534-0.63178521138-0.08101445189810.164075099951-0.2175524870790.1135841870540.02806713412360.3400939789720.0126176180353-0.04682663092520.2302234749570.007806715685510.261034966566-6.15209375054-33.5953147033-3.21170649031
55.946813344350.916323684816-0.5831494479035.156362643080.9110088060252.943872555680.06361247146950.177799456345-0.0974349199876-0.545695061409-0.102639090014-0.468173027941-0.2156290495670.4947853588580.1081944633780.2144567360180.02279532026110.01729911959950.362324905880.07536002864390.2435518972447.00772326307-32.64842333675.45500198344
63.292650853151.76170465994-0.1026451862865.673757255090.320327258322.38715866230.0742260429692-0.456590044143-0.1261411860080.211246369334-0.213762145748-0.1107653678030.003918579448910.4051780999730.1261860894930.2327211986930.0543201755042-0.02076987208130.3379675103280.07635861439960.2093431243080.20646462801-36.582575417515.6427869242
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 257 through 359 )AA257 - 3591 - 103
22chain 'A' and (resid 360 through 533 )AA360 - 533104 - 273
33chain 'B' and (resid 256 through 311 )BC256 - 3111 - 49
44chain 'B' and (resid 312 through 402 )BC312 - 40250 - 140
55chain 'B' and (resid 403 through 456 )BC403 - 456141 - 178
66chain 'B' and (resid 457 through 533 )BC457 - 533179 - 257

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