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- PDB-6l8l: C-Src in complex with ibrutinib -

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Basic information

Entry
Database: PDB / ID: 6l8l
TitleC-Src in complex with ibrutinib
ComponentsProto-oncogene tyrosine-protein kinase Src
KeywordsTRANSFERASE / kinase
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 / Recycling pathway of L1 / 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 / 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 / regulation of cell cycle / cell adhesion / cell cycle / phosphorylation / signaling receptor binding / focal adhesion / innate immune response / 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-1E8 / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesGallus gallus (chicken)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.888 Å
AuthorsGuo, M. / Dai, S. / Chen, L. / Chen, Y.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China81372904 China
National Natural Science Foundation of China81570537 China
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2020
Title: Characterization of ibrutinib as a non-covalent inhibitor of SRC-family kinases.
Authors: Guo, M. / Dai, S. / Wu, D. / Duan, Y. / Li, J. / Qu, L. / Jiang, L. / Chen, Z. / Chen, X. / Chen, Y.
History
DepositionNov 6, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 11, 2020Provider: repository / Type: Initial release
Revision 1.1Feb 3, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _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 1.2Nov 22, 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

Downloads & links

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,6698
Polymers130,9074
Non-polymers1,7624
Water18010
1
A: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,1672
Polymers32,7271
Non-polymers4401
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)33,1672
Polymers32,7271
Non-polymers4401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,1672
Polymers32,7271
Non-polymers4401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Proto-oncogene tyrosine-protein kinase Src
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,1672
Polymers32,7271
Non-polymers4401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.604, 63.407, 113.922
Angle α, β, γ (deg.)89.970, 89.940, 90.030
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.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Gallus gallus (chicken) / Gene: SRC / Production host: Escherichia coli K-12 (bacteria)
References: UniProt: P00523, non-specific protein-tyrosine kinase
#2: Chemical
ChemComp-1E8 / 1-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-one / Imbruvica / PCI-32765 / Ibrutinib


Mass: 440.497 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H24N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 10 / 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: 2.35 Å3/Da / Density % sol: 47.68 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / Details: PEG 4000

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.987 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 21, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.888→42.6 Å / Num. obs: 25440 / % possible obs: 95.07 % / Redundancy: 3.8 % / CC1/2: 0.985 / Rmerge(I) obs: 0.1473 / Rrim(I) all: 0.1711 / Net I/σ(I): 11.79
Reflection shellResolution: 2.888→2.991 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.5628 / Mean I/σ(I) obs: 7.35 / Num. unique obs: 2149 / CC1/2: 0.869 / % possible all: 80.67

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
HKL-2000data scaling
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHENIX1.15.2_3472phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4U5J

4u5j


Resolution: 2.888→42.383 Å / SU ML: 0.31 / Cross valid method: THROUGHOUT / σ(F): 1.98 / Phase error: 32.18 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2864 1390 5.47 %
Rwork0.2382 24029 -
obs0.2411 25419 94.99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 141.45 Å2 / Biso mean: 58.3974 Å2 / Biso min: 9.27 Å2
Refinement stepCycle: final / Resolution: 2.888→42.383 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8251 0 132 10 8393
Biso mean--53.78 38.88 -
Num. residues----1028
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.89-2.99110.3692980.2756205181
2.9911-3.11080.34011020.2546242994
3.1108-3.25240.33311500.2557239494
3.2524-3.42380.30411130.249241196
3.4238-3.63820.30971600.25245997
3.6382-3.91890.3481290.2433246497
3.9189-4.31290.28191480.2303243096
4.3129-4.93620.26411690.2136237895
4.9362-6.2160.30871890.24292490100
6.216-42.380.20021320.2242252399
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)
11.5666-0.00030.4790.42020.14071.35820.1782-0.39330.07690.15-0.0094-0.04390.1775-0.05910.10981.2451-0.1041-0.16120.3193-0.09630.29850.942210.24917.712
21.0749-0.59130.53552.95861.20091.1246-0.1925-0.23910.05111.254-0.04750.00140.4414-0.0695-0.02070.3789-0.03650.02390.2009-0.07420.28914.2131.05084.3205
31.4467-0.18150.09012.0435-0.10260.79180.1231-0.0464-0.11170.0354-0.24310.6741-0.0802-0.20370.0670.0835-0.05260.02110.216-0.07930.2884-4.9836-0.9341-10.2779
41.7310.2433-0.92170.3613-0.45821.0350.00820.66530.2534-0.3733-0.06860.10460.0862-0.0541-0.08771.15670.1207-0.15080.5110.09810.36411.98945.3617-36.8429
51.16470.10440.42662.5496-0.78171.8784-0.06490.5719-0.0278-1.1031-0.09250.0516-0.02550.10120.1150.626-0.0464-0.00560.2989-0.01720.29784.336834.6251-28.6714
62.7985-0.0288-0.09123.42540.35493.1357-0.40970.2662-0.0403-0.58550.06550.05360.23960.24880.26930.3879-0.04290.00170.18420.05890.25626.46231.6725-23.3805
70.5819-0.4784-0.19111.17940.48770.5996-0.24290.63980.1753-0.446-0.4161-0.3202-0.06780.00920.37790.1820.03080.0220.37770.00620.654320.154235.3017-19.2991
81.0912-0.31220.03492.8782-0.62722.510.0383-0.16290.22540.2904-0.2663-0.5376-0.47370.30010.05110.12890.04090.05140.21260.0310.256614.034535.972-7.3564
91.29560.590.41351.9225-0.08031.19970.31330.1206-0.30640.1625-0.3661-0.6714-0.0271-0.12130.04490.1629-0.00820.01930.1721-0.00210.3347.148623.4202-7.1418
101.1953-0.08190.33940.546-0.30630.24230.1711-0.3612-0.15610.25580.10390.25950.0415-0.2811-0.16021.2634-0.02950.22740.42010.22910.3893-13.6643-4.6692-39.4002
111.8675-1.41870.47751.6740.01610.35460.0767-0.18630.07260.78170.14310.030.28660.19010.50291.14570.0283-0.00430.19730.040.4553-4.89684.3506-39.7247
121.1242-0.2694-0.41643.5513-0.77241.1545-0.177-0.4592-0.17190.6669-0.02420.2457-0.0712-0.2184-0.08130.0762-0.01590.04910.28240.02190.1933-16.21066.7337-59.384
131.6350.147-0.18652.86810.32331.586-0.1385-0.1786-0.04920.8456-0.2199-0.1165-0.31330.06930.0910.473-0.132-0.03790.11420.01050.1812-9.21727.5283-53.7319
140.3578-0.0912-0.28020.23550.07930.34550.1112-0.13060.13490.3105-0.2048-0.3524-0.10770.1541-0.01950.3284-0.1148-0.21360.18610.07120.77524.6724.3379-57.7549
150.34470.2859-0.04960.7677-0.15531.2637-0.1528-0.071-0.0242-0.03630.0325-0.64350.04850.37180.01370.0085-0.0069-0.00890.3764-0.06920.3443-1.61633.4579-69.5841
162.3626-1.067-0.30291.9681-0.43781.29340.27730.14280.1746-0.0148-0.349-0.4050.14870.15960.10880.2155-0.0827-0.00010.11110.0420.198-8.507816.0368-69.8455
171.3963-0.22221.10291.9657-0.53921.1380.41380.6103-0.179-0.6076-0.15830.25870.09630.3344-0.19141.0582-0.01770.17690.3847-0.20720.4662-9.506927.1128-94.1947
181.9841-0.53440.66670.56390.152.1384-0.06320.37110.0147-0.7589-0.25090.5365-0.0753-0.26930.22570.9537-0.1419-0.0120.45880.15720.8583-19.97838.6046-92.8743
191.6025-0.2023-0.38323.4812-0.33522.65990.4020.4558-0.2416-0.6815-0.0278-0.15330.26440.4484-0.21320.31490.00620.0350.24340.02290.4644-8.674631.7121-83.051
202.19760.236-1.11692.06820.3092.3137-0.2090.52150.1316-0.6545-0.07670.0621-0.1505-0.44690.09260.4165-0.0566-0.08460.1458-00.203-13.432842.2574-77.9334
212.572-0.4086-0.55782.293-0.64750.36630.0250.9935-0.0823-0.3971-0.3732-0.0297-0.056-0.16760.07460.16330.1099-0.10960.3564-0.07450.4749-28.356936.0205-76.2668
221.5938-0.6620.03152.27260.71721.8052-0.029-0.2649-0.35350.2275-0.19850.52870.3916-0.21630.03520.10770.0181-0.03320.2505-0.06660.2205-22.253135.129-64.2944
231.05370.4002-0.71361.96470.01151.3306-0.05390.09890.28980.2451-0.20780.2004-0.0157-0.08570.09970.14060.0301-0.02320.2017-0.04210.4341-15.347747.726-64.1088
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 261 through 314 )A261 - 314
2X-RAY DIFFRACTION2chain 'A' and (resid 315 through 402 )A315 - 402
3X-RAY DIFFRACTION3chain 'A' and (resid 403 through 533 )A403 - 533
4X-RAY DIFFRACTION4chain 'B' and (resid 263 through 286 )B263 - 286
5X-RAY DIFFRACTION5chain 'B' and (resid 287 through 379 )B287 - 379
6X-RAY DIFFRACTION6chain 'B' and (resid 380 through 402 )B380 - 402
7X-RAY DIFFRACTION7chain 'B' and (resid 403 through 440 )B403 - 440
8X-RAY DIFFRACTION8chain 'B' and (resid 441 through 488 )B441 - 488
9X-RAY DIFFRACTION9chain 'B' and (resid 489 through 533 )B489 - 533
10X-RAY DIFFRACTION10chain 'C' and (resid 261 through 297 )C261 - 297
11X-RAY DIFFRACTION11chain 'C' and (resid 298 through 338 )C298 - 338
12X-RAY DIFFRACTION12chain 'C' and (resid 339 through 379 )C339 - 379
13X-RAY DIFFRACTION13chain 'C' and (resid 380 through 402 )C380 - 402
14X-RAY DIFFRACTION14chain 'C' and (resid 403 through 440 )C403 - 440
15X-RAY DIFFRACTION15chain 'C' and (resid 441 through 488 )C441 - 488
16X-RAY DIFFRACTION16chain 'C' and (resid 489 through 533 )C489 - 533
17X-RAY DIFFRACTION17chain 'D' and (resid 262 through 297 )D262 - 297
18X-RAY DIFFRACTION18chain 'D' and (resid 298 through 324 )D298 - 324
19X-RAY DIFFRACTION19chain 'D' and (resid 325 through 359 )D325 - 359
20X-RAY DIFFRACTION20chain 'D' and (resid 360 through 402 )D360 - 402
21X-RAY DIFFRACTION21chain 'D' and (resid 403 through 440 )D403 - 440
22X-RAY DIFFRACTION22chain 'D' and (resid 441 through 488 )D441 - 488
23X-RAY DIFFRACTION23chain 'D' and (resid 489 through 533 )D489 - 533

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