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- PDB-7wf5: c-Src in complex with ponatinib -

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Basic information

Entry
Database: PDB / ID: 7wf5
Titlec-Src in complex with ponatinib
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsONCOPROTEIN / Inhibitor / Kinase
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 / Co-stimulation by CD28 ...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 / Co-stimulation by CD28 / Co-inhibition by CTLA4 / 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 / immune system process / progesterone receptor signaling pathway / negative regulation of extrinsic apoptotic signaling pathway / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / epidermal growth factor receptor signaling pathway / cell junction / cell-cell junction / protein tyrosine kinase activity / protein phosphatase binding / cell differentiation / cytoskeleton / mitochondrial inner membrane / regulation of cell cycle / cell adhesion / endosome membrane / signaling receptor binding / focal adhesion / heme binding / perinuclear region of cytoplasm / protein-containing complex / ATP binding / nucleus / membrane / plasma membrane / cytosol
Similarity search - Function
: / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / Src homology 3 domains / 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 / SH2 domain superfamily / Src homology 3 domains / 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-0LI / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesGallus gallus (chicken)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.798 Å
AuthorsGuo, M. / Duan, Y. / Dai, S. / Chen, X. / Chen, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81570537 China
CitationJournal: Biochem.Biophys.Res.Commun. / Year: 2022
Title: Structural study of ponatinib in inhibiting SRC kinase.
Authors: Guo, M. / Duan, Y. / Dai, S. / Li, J. / Chen, X. / Qu, L. / Chen, Z. / Wei, H. / Jiang, L. / Chen, Y.
History
DepositionDec 26, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 2, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_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
B: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,5184
Polymers65,4532
Non-polymers1,0652
Water8,791488
1
A: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,2592
Polymers32,7271
Non-polymers5331
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)33,2592
Polymers32,7271
Non-polymers5331
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.927, 63.632, 74.505
Angle α, β, γ (deg.)79.140, 89.500, 88.800
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 257 through 263 or (resid 264...
21(chain B and (resid 257 through 276 or (resid 277...

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11LYSLYSPROPRO(chain A and (resid 257 through 263 or (resid 264...AA257 - 26310 - 16
12ARGARGARGARG(chain A and (resid 257 through 263 or (resid 264...AA26417
13LYSLYSLEULEU(chain A and (resid 257 through 263 or (resid 264...AA257 - 53310 - 286
14LYSLYSLEULEU(chain A and (resid 257 through 263 or (resid 264...AA257 - 53310 - 286
15LYSLYSLEULEU(chain A and (resid 257 through 263 or (resid 264...AA257 - 53310 - 286
16LYSLYSLEULEU(chain A and (resid 257 through 263 or (resid 264...AA257 - 53310 - 286
21LYSLYSGLYGLY(chain B and (resid 257 through 276 or (resid 277...BB257 - 27610 - 29
22CYSCYSCYSCYS(chain B and (resid 257 through 276 or (resid 277...BB27730

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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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Gallus gallus (chicken) / Gene: SRC / Production host: Escherichia coli (E. coli)
References: UniProt: P00523, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-0LI / 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzam ide / Ponatinib


Mass: 532.559 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H27F3N6O / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 488 / Source method: isolated from a natural source / Formula: H2O
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: 3.24 Å3/Da / Density % sol: 62.01 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.1M MES (pH 6.4), 50mM sodium acetate, 10mM MgCl2, 2% glycerol, 8% PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.97918 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 1, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.798→50 Å / Num. obs: 68050 / % possible obs: 96.79 % / Redundancy: 3.8 % / Biso Wilson estimate: 21.65 Å2 / Rmerge(I) obs: 0.087 / Rpim(I) all: 0.051 / Rrim(I) all: 0.101 / Rsym value: 0.063 / Net I/σ(I): 23.23
Reflection shellResolution: 1.798→1.83 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.858 / Num. unique obs: 3354 / CC1/2: 0.685 / CC star: 0.902 / Rpim(I) all: 0.512 / Rsym value: 0.692 / % possible all: 95.9

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
PDB_EXTRACT3.27data extraction
HKL-3000data reduction
HKL-3000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OIQ

2oiq


Resolution: 1.798→30.909 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.96 / Phase error: 20.72 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1826 2010 2.96 %
Rwork0.1623 66008 -
obs0.1629 68018 96.73 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 108.91 Å2 / Biso mean: 33.4998 Å2 / Biso min: 11.28 Å2
Refinement stepCycle: final / Resolution: 1.798→30.909 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4182 0 78 488 4748
Biso mean--23.59 41.48 -
Num. residues----526
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A1602X-RAY DIFFRACTION4.576TORSIONAL
12B1602X-RAY DIFFRACTION4.576TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.798-1.84270.31541320.2645438590
1.8427-1.89260.28651440.2394467996
1.8926-1.94820.25581400.2188466596
1.9482-2.01110.22841490.1942476097
2.0111-2.0830.191400.1792472297
2.083-2.16640.24061450.1621467297
2.1664-2.26490.20741470.1683476497
2.2649-2.38430.19451420.1613472197
2.3843-2.53360.17311440.1659478898
2.5336-2.72910.20831460.1667475198
2.7291-3.00360.18911470.1672477298
3.0036-3.43770.1691490.1544478998
3.4377-4.32920.1481440.1375475998
4.3292-30.9090.13821410.142478198
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)
11.56470.62930.56092.9370.04725.6330.00470.34350.124-0.78470.1280.06670.1206-0.23530.01880.5258-0.02490.00340.33460.04760.1348-7.261337.6221-21.1419
24.1425-2.8255-1.73673.1457-0.56333.1961-0.112-0.23890.4684-0.24610.298-0.0378-0.269-0.20950.04770.3876-0.0075-0.01040.30840.04690.1984-6.927941.8495-12.5098
32.32160.38870.49935.4757-0.23565.3802-0.17030.12950.7157-0.247-0.0296-0.445-0.27050.5517-0.03870.3777-0.02190.01710.33430.11020.2981-0.97741.6103-14.5728
41.2399-0.42250.20991.7445-1.17623.60480.06550.38520.1151-0.8971-0.1765-0.37340.41270.40060.10420.47610.05220.11210.35570.02480.23950.701831.0979-14.8045
51.4720.16420.1072.5763-1.01853.58120.0840.07280.2842-0.08950.07650.2112-0.0433-0.2672-0.06180.13230.0338-0.00460.16370.00540.1953-10.599236.68062.6458
61.9741-0.13180.01671.884-0.25762.1959-0.04540.120.0454-0.2005-0.0177-0.22980.05310.16520.04340.1590.00870.04010.1349-0.00470.15532.672528.63074.4246
73.6532-0.4406-0.2314.0574-0.46242.7857-0.0018-0.35320.27330.254-0.0249-0.7765-0.31580.44820.03090.2014-0.0468-0.03960.2311-0.05830.35768.899138.593116.6914
82.70470.1605-0.72123.98950.02863.0063-0.0623-0.3161-0.02710.2352-0.0938-0.39680.00710.32380.09060.18320.0241-0.03710.20440.02440.18796.585125.243418.0078
92.57370.2917-0.26685.3503-0.35072.6293-0.0259-0.1598-0.10570.4459-0.02790.31990.0605-0.15640.11640.2089-0.00140.02780.1669-0.00290.176-7.524419.962516.2906
101.8481.223-2.79431.8789-0.68445.45760.2342-0.2450.35110.85790.1273-0.0152-0.85250.1134-0.31870.6351-0.0239-0.06610.3327-0.01260.2494-1.841770.440743.4494
111.13920.0637-0.16422.3286-0.3262.6657-0.0114-0.16950.09330.3610.0542-0.0468-0.2006-0.0068-0.06120.14920.0165-0.01220.1609-0.010.1565-4.343263.498930.1252
122.2944-0.46660.9230.2003-0.46141.2704-0.1881-0.00750.16970.08490.05780.2115-0.174-0.19510.12070.15040.01260.00030.2149-0.00720.2686-19.399366.022121.0542
131.4778-0.802-0.19093.1069-0.58671.23330.03610.1715-0.0042-0.2551-0.03390.1033-0.0032-0.0564-0.01590.147-0.0172-0.01950.1669-0.02670.1435-10.117259.33749.812
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 257 through 272 )A257 - 272
2X-RAY DIFFRACTION2chain 'A' and (resid 273 through 289 )A273 - 289
3X-RAY DIFFRACTION3chain 'A' and (resid 290 through 303 )A290 - 303
4X-RAY DIFFRACTION4chain 'A' and (resid 304 through 334 )A304 - 334
5X-RAY DIFFRACTION5chain 'A' and (resid 335 through 359 )A335 - 359
6X-RAY DIFFRACTION6chain 'A' and (resid 360 through 456 )A360 - 456
7X-RAY DIFFRACTION7chain 'A' and (resid 457 through 476 )A457 - 476
8X-RAY DIFFRACTION8chain 'A' and (resid 477 through 508 )A477 - 508
9X-RAY DIFFRACTION9chain 'A' and (resid 509 through 533 )A509 - 533
10X-RAY DIFFRACTION10chain 'B' and (resid 254 through 289 )B254 - 289
11X-RAY DIFFRACTION11chain 'B' and (resid 290 through 402 )B290 - 402
12X-RAY DIFFRACTION12chain 'B' and (resid 403 through 440 )B403 - 440
13X-RAY DIFFRACTION13chain 'B' and (resid 441 through 533 )B441 - 533

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