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- PDB-6y7t: Engineered conjugation of lysine-specific molecular tweezers with... -

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Basic information

Entry
Database: PDB / ID: 6y7t
TitleEngineered conjugation of lysine-specific molecular tweezers with ExoS derived peptidic inhibitor enhance affinity towards target protein 14-3-3 through ditopic binding
Components
  • 14-3-3 protein sigma
  • Exoenzyme S
KeywordsPEPTIDE BINDING PROTEIN / Protein-protein interactions / supramolecular ligands / molecular tweezers / protein recognition / hybrid ligands
Function / homology
Function and homology information


regulation of epidermal cell division / protein kinase C inhibitor activity / positive regulation of epidermal cell differentiation / keratinocyte development / keratinization / glycosyltransferase activity / regulation of cell-cell adhesion / cAMP/PKA signal transduction / Regulation of localization of FOXO transcription factors / keratinocyte proliferation ...regulation of epidermal cell division / protein kinase C inhibitor activity / positive regulation of epidermal cell differentiation / keratinocyte development / keratinization / glycosyltransferase activity / regulation of cell-cell adhesion / cAMP/PKA signal transduction / Regulation of localization of FOXO transcription factors / keratinocyte proliferation / Activation of BAD and translocation to mitochondria / phosphoserine residue binding / negative regulation of keratinocyte proliferation / establishment of skin barrier / negative regulation of protein localization to plasma membrane / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / negative regulation of protein kinase activity / negative regulation of stem cell proliferation / RHO GTPases activate PKNs / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / positive regulation of protein localization / nucleotidyltransferase activity / positive regulation of cell adhesion / protein sequestering activity / negative regulation of innate immune response / GTPase activator activity / protein export from nucleus / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / release of cytochrome c from mitochondria / positive regulation of protein export from nucleus / stem cell proliferation / TP53 Regulates Metabolic Genes / Translocation of SLC2A4 (GLUT4) to the plasma membrane / intrinsic apoptotic signaling pathway in response to DNA damage / intracellular protein localization / regulation of protein localization / toxin activity / positive regulation of cell growth / regulation of cell cycle / cadherin binding / protein kinase binding / negative regulation of transcription by RNA polymerase II / signal transduction / extracellular space / extracellular exosome / extracellular region / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Type III secretion system effector protein YopE-like / Virulence factor YopE, GAP domain / Virulence factor YopE, GAP domain superfamily / Yersinia virulence determinant (YopE) / : / ADP ribosyltransferase / ADP-ribosyltransferase exoenzyme / Toxin-related mono-ADP-ribosyltransferase (TR mART) core domain profile. / 14-3-3 protein sigma / 14-3-3 proteins signature 2. ...Type III secretion system effector protein YopE-like / Virulence factor YopE, GAP domain / Virulence factor YopE, GAP domain superfamily / Yersinia virulence determinant (YopE) / : / ADP ribosyltransferase / ADP-ribosyltransferase exoenzyme / Toxin-related mono-ADP-ribosyltransferase (TR mART) core domain profile. / 14-3-3 protein sigma / 14-3-3 proteins signature 2. / 14-3-3 protein, conserved site / 14-3-3 proteins signature 1. / 14-3-3 protein / 14-3-3 homologues / 14-3-3 domain / 14-3-3 domain superfamily / 14-3-3 protein
Similarity search - Domain/homology
ExoSTWZ molecular tweezer / 14-3-3 protein sigma / Exoenzyme S
Similarity search - Component
Biological speciesHomo sapiens (human)
Pseudomonas aeruginosa (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsGuillory, X. / Ottmann, C.
Funding support Germany, Netherlands, 2items
OrganizationGrant numberCountry
German Research Foundation (DFG) Germany
Netherlands Organisation for Scientific Research (NWO) Netherlands
Citation
Journal: J.Am.Chem.Soc. / Year: 2021
Title: Supramolecular Enhancement of a Natural 14-3-3 Protein Ligand.
Authors: Guillory, X. / Hadrovic, I. / de Vink, P.J. / Sowislok, A. / Brunsveld, L. / Schrader, T. / Ottmann, C.
#1: Journal: J. Am. Chem. Soc. / Year: 2017
Title: The Molecular Tweezer CLR01 Stabilizes a Disordered Protein-Protein Interface.
Authors: Bier, D. / Mittal, S. / Bravo-Rodriguez, K. / Sowislok, A. / Guillory, X. / Briels, J. / Heid, C. / Bartel, M. / Wettig, B. / Brunsveld, L. / Sanchez-Garcia, E. / Schrader, T. / Ottmann, C.
#2: Journal: Nat Chem / Year: 2013
Title: Molecular tweezers modulate 14-3-3 protein-protein interactions.
Authors: Bier, D. / Rose, R. / Bravo-Rodriguez, K. / Bartel, M. / Ramirez-Anguita, J.M. / Dutt, S. / Wilch, C. / Klarner, F.G. / Sanchez-Garcia, E. / Schrader, T. / Ottmann, C.
History
DepositionMar 2, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 31, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 13, 2021Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_2 / pdbx_database_proc
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 / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Jan 24, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 14-3-3 protein sigma
D: Exoenzyme S
E: Exoenzyme S
F: 14-3-3 protein sigma
K: 14-3-3 protein sigma
P: 14-3-3 protein sigma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)117,19515
Polymers115,1376
Non-polymers2,0599
Water6,612367
1
D: Exoenzyme S
F: 14-3-3 protein sigma
P: 14-3-3 protein sigma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,6098
Polymers57,5683
Non-polymers1,0415
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: 14-3-3 protein sigma
E: Exoenzyme S
hetero molecules

K: 14-3-3 protein sigma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,5867
Polymers57,5683
Non-polymers1,0184
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555-x+1/2,y+1/2,-z+1/21
3
K: 14-3-3 protein sigma
hetero molecules

A: 14-3-3 protein sigma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,5915
Polymers56,4532
Non-polymers1383
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_545-x+1/2,y-1/2,-z+1/21
Unit cell
Length a, b, c (Å)145.151, 63.119, 167.021
Angle α, β, γ (deg.)90.00, 101.29, 90.00
Int Tables number5
Space group name H-MI121

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Components

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Protein / Protein/peptide , 2 types, 6 molecules AFKPDE

#1: Protein
14-3-3 protein sigma / Epithelial cell marker protein 1 / Stratifin


Mass: 28226.518 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SFN, HME1 / Production host: Escherichia coli (E. coli) / References: UniProt: P31947
#2: Protein/peptide Exoenzyme S


Mass: 1115.236 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Pseudomonas aeruginosa (bacteria) / References: UniProt: Q51451

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Non-polymers , 4 types, 376 molecules

#3: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Formula: Na
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-TWZ / ExoSTWZ molecular tweezer


Mass: 879.785 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C48H39N3O10P2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 367 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 3.54 Å3/Da / Density % sol: 65.21 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: Bis-Tris Propane 0.2M sodium acetate trihydrate 20% PEG1000 10% Glycerol pH 7 Grew at 4 degree Celsius after a few days

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: EMBL/DESY, HAMBURG / Beamline: X11 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Dec 14, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 2.5→59.9 Å / Num. obs: 51708 / % possible obs: 99.9 % / Redundancy: 6.6 % / Biso Wilson estimate: 34.12 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.129 / Rpim(I) all: 0.058 / Rrim(I) all: 0.151 / Net I/σ(I): 8.2
Reflection shellResolution: 2.5→2.57 Å / Redundancy: 6.4 % / Rmerge(I) obs: 0.803 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 3691 / CC1/2: 0.796 / Rpim(I) all: 0.373 / Rrim(I) all: 0.954 / % possible all: 98.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4N7G

4n7g


Resolution: 2.5→59.9 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.905 / SU B: 19.831 / SU ML: 0.229 / Cross valid method: THROUGHOUT / ESU R: 0.38 / ESU R Free: 0.275 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26754 2689 5.2 %RANDOM
Rwork0.21895 ---
obs0.2215 49026 99.75 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 46.368 Å2
Baniso -1Baniso -2Baniso -3
1-3.93 Å2-0 Å2-0.11 Å2
2---0.4 Å2-0 Å2
3----3.23 Å2
Refinement stepCycle: 1 / Resolution: 2.5→59.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7369 0 141 367 7877
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0137720
X-RAY DIFFRACTIONr_bond_other_d0.0010.0177189
X-RAY DIFFRACTIONr_angle_refined_deg1.7021.64610429
X-RAY DIFFRACTIONr_angle_other_deg1.3171.58216696
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.185948
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.38222.707410
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.361151418
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7541555
X-RAY DIFFRACTIONr_chiral_restr0.0760.2994
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.028627
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021558
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.9033.1773798
X-RAY DIFFRACTIONr_mcbond_other1.9023.1773797
X-RAY DIFFRACTIONr_mcangle_it2.974.7554744
X-RAY DIFFRACTIONr_mcangle_other2.9694.7564745
X-RAY DIFFRACTIONr_scbond_it2.5763.4493922
X-RAY DIFFRACTIONr_scbond_other2.5763.4483922
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.7615.0975686
X-RAY DIFFRACTIONr_long_range_B_refined6.23560.09931966
X-RAY DIFFRACTIONr_long_range_B_other6.22360.00731830
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.5→2.564 Å
RfactorNum. reflection% reflection
Rfree0.338 198 -
Rwork0.275 3461 -
obs--97.06 %
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)
11.15620.18280.85280.69570.25492.25930.13770.0427-0.0955-0.0067-0.0835-0.01940.2178-0.1215-0.05420.0268-0.0032-0.01110.07250.01010.08717.17350.081719.4495
24.4921-5.0059-2.20738.03870.38572.9331-0.2502-0.3205-0.35590.47640.01730.15530.050.35820.23280.1735-0.1133-0.11460.18470.13750.278824.02034.3174-18.664
31.57642.57840.49415.61972.36392.0172-0.12950.3120.0163-0.28810.2822-0.2579-0.1436-0.1213-0.15270.0491-0.0027-0.00910.19940.05790.251118.24146.202212.3908
41.6471-0.2933-1.02280.41330.02611.27710.1438-0.01430.1720.0446-0.06270.028-0.1444-0.1161-0.08110.0390.00160.05870.05950.00050.133225.925410.8091-25.4806
52.391-0.2095-0.32430.8568-0.07070.39360.108-0.10060.23830.1749-0.10440.2259-0.1084-0.1271-0.00360.0813-0.02170.0090.1203-0.01660.19895.8047-13.666550.563
62.79590.17880.66261.5716-0.09560.85790.2001-0.4153-0.34440.5219-0.1369-0.27750.24670.1268-0.06320.3366-0.0193-0.00640.14980.02350.236861.5058-7.3813-23.3276
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A-4 - 231
2X-RAY DIFFRACTION2D420 - 430
3X-RAY DIFFRACTION3E420 - 430
4X-RAY DIFFRACTION4F-4 - 231
5X-RAY DIFFRACTION5K-4 - 231
6X-RAY DIFFRACTION6P-4 - 231

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