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- PDB-3u51: Src in complex with DNA-templated macrocyclic inhibitor MC1 -

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Basic information

Entry
Database: PDB / ID: 3u51
TitleSrc in complex with DNA-templated macrocyclic inhibitor MC1
Components
  • Proto-oncogene tyrosine-protein kinase Src
  • macrocyclic inhibitor MC1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein kinase / Src-like inactive conformation / 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 / 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 / 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
(2S,5S,8S,13S,16Z)-5-(cyclohexylmethyl)-3,6,9,15,18-pentaoxo-2-(3-phenylprop-2-en-1-yl)-8-{3-[(pyrazin-2-ylcarbonyl)amino]propyl}-1,4,7,10,14-pentaazacyclooctadec-16-ene-13-carboxamide / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesGallus gallus (chicken)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.241 Å
AuthorsSeeliger, M.A. / Liu, D.R. / Georghiou, G. / Kleiner, R.E. / Pulkoski-Gross, M.
CitationJournal: Nat.Chem.Biol. / Year: 2012
Title: Highly specific, bisubstrate-competitive Src inhibitors from DNA-templated macrocycles.
Authors: Georghiou, G. / Kleiner, R.E. / Pulkoski-Gross, M. / Liu, D.R. / Seeliger, M.A.
History
DepositionOct 10, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 22, 2012Provider: repository / Type: Initial release
Revision 1.1Mar 7, 2012Group: Database references
Revision 1.2Apr 4, 2012Group: Database references
Revision 1.3Dec 12, 2012Group: Other
Revision 1.4Sep 23, 2020Group: Derived calculations / Category: struct_conn
Item: _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag ..._struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id
Revision 1.5Sep 13, 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection / Derived calculations
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / pdbx_validate_torsion / struct_conn
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2 / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_label_atom_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
C: macrocyclic inhibitor MC1
D: macrocyclic inhibitor MC1


Theoretical massNumber of molelcules
Total (without water)64,6364
Polymers64,6364
Non-polymers00
Water2,198122
1
A: Proto-oncogene tyrosine-protein kinase Src
C: macrocyclic inhibitor MC1


Theoretical massNumber of molelcules
Total (without water)32,3182
Polymers32,3182
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Proto-oncogene tyrosine-protein kinase Src
D: macrocyclic inhibitor MC1


Theoretical massNumber of molelcules
Total (without water)32,3182
Polymers32,3182
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.166, 117.250, 62.762
Angle α, β, γ (deg.)90.000, 90.080, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

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
11GLUGLUGLYGLYchain A and (resseq 261:406 or resseq 425:533 )AA261 - 4063 - 148
12PROPROLEULEUchain A and (resseq 261:406 or resseq 425:533 )AA425 - 533167 - 275
21GLUGLUGLYGLYchain B and (resseq 261:406 or resseq 425:533 )BB261 - 4063 - 148
22PROPROLEULEUchain B and (resseq 261:406 or resseq 425:533 )BB425 - 533167 - 275

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Components

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


Mass: 31557.336 Da / Num. of mol.: 2 / Fragment: Src kinase domain (UNP residues 259-533)
Source method: isolated from a genetically manipulated source
Details: as published in Protein Science 14(12):3135-3139 / Source: (gene. exp.) Gallus gallus (chicken) / Gene: SRC / Plasmid: pET28 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P00523, non-specific protein-tyrosine kinase
#2: Protein/peptide macrocyclic inhibitor MC1


Type: Peptide-like / Class: Inhibitor / Mass: 760.859 Da / Num. of mol.: 2 / Source method: obtained synthetically
References: (2S,5S,8S,13S,16Z)-5-(cyclohexylmethyl)-3,6,9,15,18-pentaoxo-2-(3-phenylprop-2-en-1-yl)-8-{3-[(pyrazin-2-ylcarbonyl)amino]propyl}-1,4,7,10,14-pentaazacyclooctadec-16-ene-13-carboxamide
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 122 / 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: 2.46 Å3/Da / Density % sol: 49.96 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.1 M Bis-Tris, pH 6.5, 12% PEG3350, 1% Tacsimate, pH 6.0, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 8, 2010
RadiationMonochromator: Rosenbaum-Rock double crystal sagittal focusing
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.075 Å / Relative weight: 1
Reflection twinOperator: h,-k,-l / Fraction: 0.382
ReflectionResolution: 2.24→50 Å / Num. all: 29255 / Num. obs: 27792 / % possible obs: 95 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.1 % / Rmerge(I) obs: 0.069 / Net I/σ(I): 14.2
Reflection shell
Resolution (Å)Diffraction-ID% possible all
2.24-2.32187
2.32-2.41193
2.41-2.52192.6
2.52-2.66192.9
2.66-2.82193.8
2.82-3.04196.7
3.04-3.35197.5
3.35-3.83198.3
3.83-4.82198.8
4.82-50199

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Processing

Software
NameVersionClassificationNB
PHENIX1.6_289refinement
PDB_EXTRACT3.1data extraction
CBASSdata collection
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1Y57

1y57


Resolution: 2.241→34.978 Å / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.7134 / σ(F): 0 / Phase error: 35.03 / Stereochemistry target values: TWIN_LSQ_F
RfactorNum. reflection% reflection
Rfree0.2364 2104 7.58 %
Rwork0.1987 25742 -
obs0.2001 27767 94.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 36.026 Å2 / ksol: 0.353 e/Å3
Displacement parametersBiso max: 168.47 Å2 / Biso mean: 52.29 Å2 / Biso min: 15.03 Å2
Baniso -1Baniso -2Baniso -3
1--3.345 Å20 Å2-1.4975 Å2
2--20.3688 Å20 Å2
3----17.0238 Å2
Refinement stepCycle: LAST / Resolution: 2.241→34.978 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4215 0 0 122 4337
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0044320
X-RAY DIFFRACTIONf_angle_d0.8275843
X-RAY DIFFRACTIONf_chiral_restr0.06623
X-RAY DIFFRACTIONf_plane_restr0.003753
X-RAY DIFFRACTIONf_dihedral_angle_d14.2421629
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDTypeRms dev position (Å)
11A2048X-RAY DIFFRACTIONPOSITIONAL0.05
12B2048X-RAY DIFFRACTIONPOSITIONAL0.05
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 15

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.241-2.29310.37741210.33231502162377
2.2931-2.35040.29231290.30771654178385
2.3504-2.4140.31391290.29831659178886
2.414-2.4850.31531330.29861704183787
2.485-2.56510.28531250.27541636176186
2.5651-2.65680.2721320.27171690182286
2.6568-2.76310.30331340.26421690182486
2.7631-2.88880.32781300.24081710184089
2.8888-3.0410.28051390.22611763190290
3.041-3.23140.27361410.21541750189190
3.2314-3.48060.24411420.17861787192991
3.4806-3.83040.18571400.16311783192391
3.8304-4.38360.20771400.13781783192392
4.3836-5.51880.18581460.15111792193891
5.5188-33.18010.19541400.17131839197992
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)
11.1112-0.25790.1040.485-0.4480.43340.0478-0.2632-0.3589-0.110.01390.08360.14460.0777-0.03370.51680.08420.02260.50930.12620.4667-16.87888.38265.9818
20.38680.1302-0.23590.2841-0.2860.3752-0.07750.0412-0.011-0.0698-0.0021-0.03530.18160.08760.02760.19820.0182-0.00330.2674-0.02080.1377-13.514522.1379-2.4452
30.1658-0.0373-0.10860.16550.13440.13910.0471-0.1213-0.0392-0.0076-0.13710.15730.0432-0.18790.05260.067-0.01990.02520.5395-0.00280.2164-27.039333.85160.7692
40.00370.0170.01710.101-0.05370.3011-0.00620.05450.1823-0.0125-0.05940.0402-0.0868-0.0480.01220.0723-0.0073-0.0150.434700.2206-18.036140.7048-9.7195
50.14040.2343-0.26620.512-0.14241.24720.05260.15240.0404-0.1531-0.0383-0.0209-0.3762-0.25060.03120.68890.040.1030.5967-0.08330.4817-15.234864.6092-22.2946
60.4680.0412-0.05480.277-0.13120.0679-0.0047-0.13580.01960.4013-0.0147-0.0630.00480.05680.00590.57010.0721-0.07210.5614-0.25180.4013-11.787464.2386-24.5384
70.733-0.09590.34571.648-0.39973.66420.1992-0.20670.4323-0.13320.3364-0.2814-0.13430.0739-0.48610.8622-0.13130.06791.0797-0.14020.9764-1.108465.2945-33.7227
81.1605-0.4235-0.13690.3023-0.36281.20710.0571-0.1558-0.02530.09760.18230.0356-0.3124-0.1657-0.17030.41140.02290.03190.4883-0.0140.3472-11.274962.7279-34.2724
90.3183-0.01810.11070.18730.16260.34430.0427-0.15860.0470.02860.0516-0.0581-0.0845-0.15490.06170.09160.0117-0.01150.33-0.00940.1551-14.799447.7442-33.8665
100.10930.03370.21210.1010.0430.4047-0.046-0.1046-0.08860.00280.0153-0.04140.0081-0.1623-0.0030.1219-0.0455-0.00280.38940.01570.2294-1.989340.3262-31.8207
110.23090.15940.04950.20130.11480.10950.0304-0.1281-0.05470.0743-0.0211-0.09210.061-0.104-0.04670.0270.0065-0.10450.52670.03790.1539-0.139529.9068-29.7019
120.3168-0.25250.09780.26670.00230.32350.10310.33790.0325-0.0533-0.0891-0.07830.04160.04220.02470.1266-0.014-0.01650.4755-0.05170.1969-10.345333.4331-43.127
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resseq 261:316)A261 - 316
2X-RAY DIFFRACTION2chain 'A' and (resseq 317:402)A317 - 402
3X-RAY DIFFRACTION3chain 'A' and (resseq 403:476)A403 - 476
4X-RAY DIFFRACTION4chain 'A' and (resseq 477:533)A477 - 533
5X-RAY DIFFRACTION5chain 'B' and (resseq 261:286)B261 - 286
6X-RAY DIFFRACTION6chain 'B' and (resseq 287:303)B287 - 303
7X-RAY DIFFRACTION7chain 'B' and (resseq 304:316)B304 - 316
8X-RAY DIFFRACTION8chain 'B' and (resseq 317:333)B317 - 333
9X-RAY DIFFRACTION9chain 'B' and (resseq 334:402)B334 - 402
10X-RAY DIFFRACTION10chain 'B' and (resseq 403:467)B403 - 467
11X-RAY DIFFRACTION11chain 'B' and (resseq 468:488)B468 - 488
12X-RAY DIFFRACTION12chain 'B' and (resseq 489:533)B489 - 533

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