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- PDB-5bmm: Src in complex with DNA-templated macrocyclic inhibitor MC25b -

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Basic information

Entry
Database: PDB / ID: 5bmm
TitleSrc in complex with DNA-templated macrocyclic inhibitor MC25b
Components
  • Proto-oncogene tyrosine-protein kinase Src
  • macrocyclic inhibitor MC25b
KeywordsTransferase/transferase Inhibitor / 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
macrocyclic inhibitor MC25b / Proto-oncogene tyrosine-protein kinase Src
Similarity search - Component
Biological speciesGallus gallus (chicken)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsGeorghiou, G. / Guja, K.E. / Aleem, S. / Kleiner, R.E. / Liu, D.R. / Miller, W.T. / Garcia-Diaz, M. / Seeliger, M.A.
CitationJournal: Cell Chem Biol / Year: 2016
Title: Structural and Biochemical Basis for Intracellular Kinase Inhibition by Src-specific Peptidic Macrocycles.
Authors: Aleem, S.U. / Georghiou, G. / Kleiner, R.E. / Guja, K.E. / Craddock, B.P. / Lyczek, A. / Chan, A.I. / Garcia-Diaz, M. / Miller, W.T. / Liu, D.R. / Seeliger, M.A.
History
DepositionMay 22, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 21, 2016Provider: repository / Type: Initial release
Revision 1.1Oct 5, 2016Group: Database references
Revision 1.2Sep 27, 2023Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list / pdbx_validate_polymer_linkage / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_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 / 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

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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 MC25b
D: macrocyclic inhibitor MC25b


Theoretical massNumber of molelcules
Total (without water)66,9354
Polymers66,9354
Non-polymers00
Water2,342130
1
A: Proto-oncogene tyrosine-protein kinase Src
C: macrocyclic inhibitor MC25b


Theoretical massNumber of molelcules
Total (without water)33,4672
Polymers33,4672
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1570 Å2
ΔGint-1 kcal/mol
Surface area12150 Å2
MethodPISA
2
B: Proto-oncogene tyrosine-protein kinase Src
D: macrocyclic inhibitor MC25b


Theoretical massNumber of molelcules
Total (without water)33,4672
Polymers33,4672
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1610 Å2
ΔGint-1 kcal/mol
Surface area12210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.830, 118.610, 42.650
Angle α, β, γ (deg.)90.00, 90.08, 90.00
Int Tables number4
Space group name H-MP1211

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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 BL21(DE3) (bacteria)
References: UniProt: P00523, non-specific protein-tyrosine kinase
#2: Protein/peptide macrocyclic inhibitor MC25b


Type: Peptide-like / Class: Inhibitor / Mass: 740.776 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) / References: macrocyclic inhibitor MC25b
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 130 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.41 Å3/Da / Density % sol: 48.97 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 14% PEG 5000 MME, 0.3 M NaH2PO

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 9, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.075 Å / Relative weight: 1
ReflectionResolution: 2.5→42.65 Å / Num. obs: 17499 / % possible obs: 83.9 % / Redundancy: 7.4 % / Rmerge(I) obs: 0.252 / Net I/σ(I): 8.2
Reflection shellResolution: 2.5→2.59 Å / Redundancy: 6.7 % / Rmerge(I) obs: 0.67 / Mean I/σ(I) obs: 3 / % possible all: 26.6

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3U4W

3u4w


Resolution: 2.5→42.65 Å / SU ML: 0.35 / Cross valid method: FREE R-VALUE / σ(F): 1.4 / Phase error: 25.19 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.246 871 4.98 %RANDOM
Rwork0.218 ---
obs0.22 17497 83.7 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.5→42.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4404 0 0 130 4534
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0034512
X-RAY DIFFRACTIONf_angle_d0.8316131
X-RAY DIFFRACTIONf_dihedral_angle_d14.8661653
X-RAY DIFFRACTIONf_chiral_restr0.03667
X-RAY DIFFRACTIONf_plane_restr0.004792
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5006-2.65730.3358740.27671189X-RAY DIFFRACTION36
2.6573-2.86240.3081060.29162295X-RAY DIFFRACTION69
2.8624-3.15040.2991630.25863153X-RAY DIFFRACTION96
3.1504-3.6060.24971840.21973324X-RAY DIFFRACTION100
3.606-4.54240.21451590.18753309X-RAY DIFFRACTION100
4.54-42.650.20821850.19123356X-RAY DIFFRACTION100
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)
11.3956-0.15-0.21281.37830.17071.8206-0.0994-0.1699-0.20570.07230.05970.03860.2277-0.0120.05340.16610.011-0.02710.33140.01720.206-28.413-1.1445-7.3556
21.5981-0.04240.01521.45320.27271.4995-0.03030.16810.1896-0.02780.00520.0348-0.144-0.0810.0010.12760.00410.0140.3771-0.00020.2086-58.615719.7768-23.1846
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN A
2X-RAY DIFFRACTION2CHAIN B

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