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- PDB-6t2e: Multicomponent Peptide Stapling as a Diversity-Driven Tool for th... -

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Basic information

Entry
Database: PDB / ID: 6t2e
TitleMulticomponent Peptide Stapling as a Diversity-Driven Tool for the Development of Inhibitors of Protein-Protein Interactions
Components
  • E3 ubiquitin-protein ligase Mdm2
  • Stapled peptide GAR300-Gm
KeywordsPEPTIDE BINDING PROTEIN / Inhibitor / Complex / MDM2 / Stapled peptides / Ugi MCR-based macrocyclizations
Function / homology
Function and homology information


cellular response to vitamin B1 / response to formaldehyde / response to water-immersion restraint stress / traversing start control point of mitotic cell cycle / response to ether / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / negative regulation of signal transduction by p53 class mediator / fibroblast activation / atrial septum development / receptor serine/threonine kinase binding ...cellular response to vitamin B1 / response to formaldehyde / response to water-immersion restraint stress / traversing start control point of mitotic cell cycle / response to ether / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / negative regulation of signal transduction by p53 class mediator / fibroblast activation / atrial septum development / receptor serine/threonine kinase binding / Trafficking of AMPA receptors / positive regulation of vascular associated smooth muscle cell migration / peroxisome proliferator activated receptor binding / SUMO transferase activity / negative regulation of protein processing / response to iron ion / response to steroid hormone / NEDD8 ligase activity / cellular response to peptide hormone stimulus / AKT phosphorylates targets in the cytosol / atrioventricular valve morphogenesis / ventricular septum development / endocardial cushion morphogenesis / positive regulation of muscle cell differentiation / cellular response to alkaloid / SUMOylation of ubiquitinylation proteins / regulation of protein catabolic process / blood vessel development / cardiac septum morphogenesis / ligase activity / Constitutive Signaling by AKT1 E17K in Cancer / negative regulation of DNA damage response, signal transduction by p53 class mediator / SUMOylation of transcription factors / response to magnesium ion / protein sumoylation / protein localization to nucleus / cellular response to UV-C / blood vessel remodeling / cellular response to estrogen stimulus / protein autoubiquitination / cellular response to actinomycin D / ribonucleoprotein complex binding / positive regulation of vascular associated smooth muscle cell proliferation / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / transcription repressor complex / NPAS4 regulates expression of target genes / regulation of heart rate / positive regulation of mitotic cell cycle / positive regulation of protein export from nucleus / proteolysis involved in protein catabolic process / ubiquitin binding / response to cocaine / Stabilization of p53 / Regulation of RUNX3 expression and activity / protein destabilization / establishment of protein localization / RING-type E3 ubiquitin transferase / Oncogene Induced Senescence / cellular response to gamma radiation / Regulation of TP53 Activity through Methylation / cellular response to growth factor stimulus / cellular response to hydrogen peroxide / response to toxic substance / protein polyubiquitination / ubiquitin-protein transferase activity / disordered domain specific binding / endocytic vesicle membrane / ubiquitin protein ligase activity / p53 binding / Signaling by ALK fusions and activated point mutants / Regulation of TP53 Degradation / negative regulation of neuron projection development / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / 5S rRNA binding / cellular response to hypoxia / ubiquitin-dependent protein catabolic process / regulation of gene expression / protein-containing complex assembly / Oxidative Stress Induced Senescence / proteasome-mediated ubiquitin-dependent protein catabolic process / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / regulation of cell cycle / Ub-specific processing proteases / protein ubiquitination / response to xenobiotic stimulus / protein domain specific binding / response to antibiotic / negative regulation of DNA-templated transcription / ubiquitin protein ligase binding / positive regulation of cell population proliferation / positive regulation of gene expression / negative regulation of apoptotic process / nucleolus / apoptotic process / negative regulation of transcription by RNA polymerase II / enzyme binding / protein-containing complex / zinc ion binding / nucleoplasm
Similarity search - Function
MDM2 / SWIB/MDM2 domain / E3 ubiquitin-protein ligase Mdm2 / MDM2, modified RING finger, HC subclass / p53 negative regulator Mdm2/Mdm4 / SWIB/MDM2 domain / SWIB/MDM2 domain / SWIB/MDM2 domain profile. / SWIB/MDM2 domain superfamily / Zn-finger in Ran binding protein and others ...MDM2 / SWIB/MDM2 domain / E3 ubiquitin-protein ligase Mdm2 / MDM2, modified RING finger, HC subclass / p53 negative regulator Mdm2/Mdm4 / SWIB/MDM2 domain / SWIB/MDM2 domain / SWIB/MDM2 domain profile. / SWIB/MDM2 domain superfamily / Zn-finger in Ran binding protein and others / Zinc finger, C3HC4 type (RING finger) / Zinc finger RanBP2 type profile. / Zinc finger RanBP2-type signature. / Zinc finger, RanBP2-type superfamily / Zinc finger, RanBP2-type / Zinc finger RING-type profile. / Zinc finger, RING-type / Zinc finger, RING/FYVE/PHD-type / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsGroves, R.M. / Ali, M.A. / Atmaj, J. / van Oosterwijk, N. / Domling, A. / Rivera, G.D. / Ricardo, G.M.
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2020
Title: Multicomponent Peptide Stapling as a Diversity-Driven Tool for the Development of Inhibitors of Protein-Protein Interactions.
Authors: Ricardo, M.G. / Ali, A.M. / Plewka, J. / Surmiak, E. / Labuzek, B. / Neochoritis, C.G. / Atmaj, J. / Skalniak, L. / Zhang, R. / Holak, T.A. / Groves, M. / Rivera, D.G. / Domling, A.
History
DepositionOct 8, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 29, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 25, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.2Jan 24, 2024Group: 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: E3 ubiquitin-protein ligase Mdm2
B: Stapled peptide GAR300-Gm


Theoretical massNumber of molelcules
Total (without water)11,8492
Polymers11,8492
Non-polymers00
Water45025
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: MST, Microscale Thermophoresis
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1380 Å2
ΔGint-15 kcal/mol
Surface area5910 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.285, 39.285, 215.321
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122

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Components

#1: Protein E3 ubiquitin-protein ligase Mdm2 / Double minute 2 protein / Hdm2 / Oncoprotein Mdm2 / RING-type E3 ubiquitin transferase Mdm2 / p53- ...Double minute 2 protein / Hdm2 / Oncoprotein Mdm2 / RING-type E3 ubiquitin transferase Mdm2 / p53-binding protein Mdm2


Mass: 10192.040 Da / Num. of mol.: 1 / Mutation: L33E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q00987, RING-type E3 ubiquitin transferase
#2: Protein/peptide Stapled peptide GAR300-Gm


Mass: 1656.789 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: The current X-ray structure does not include the stapled linker due to insufficient electron density. The staple was modeled by MOLOC software.
Source: (synth.) synthetic construct (others)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 25 / 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: 2.02 Å3/Da / Density % sol: 39.23 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 8.2
Details: 0.056 M Sodium phosphate monobasic monohydrate, 1.344 M Potassium phosphate dibasic, pH8.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, DESY / Beamline: P11 / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jun 16, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.4→43.06 Å / Num. obs: 4256 / % possible obs: 95.3 % / Redundancy: 5.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.041 / Rpim(I) all: 0.017 / Rrim(I) all: 0.044 / Net I/σ(I): 31.3 / Num. measured all: 24240 / Scaling rejects: 1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.4-2.4960.12626034360.9910.0490.13613.897
8.98-43.063.90.01945111710.010.02247.787.6

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Processing

Software
NameVersionClassification
REFMACrefmac_5.8.0230refinement
XDSdata reduction
Aimless0.7.1data scaling
PDB_EXTRACT3.25data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1RV1

1rv1


Resolution: 2.4→34.04 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.869 / SU B: 20.363 / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.637 / ESU R Free: 0.333
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2902 186 4.5 %RANDOM
Rwork0.2124 ---
obs0.2157 3980 94.1 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 68.11 Å2 / Biso mean: 26.401 Å2 / Biso min: 12.41 Å2
Baniso -1Baniso -2Baniso -3
1--0.03 Å2-0.02 Å20 Å2
2---0.03 Å20 Å2
3---0.11 Å2
Refinement stepCycle: final / Resolution: 2.4→34.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms824 0 0 25 849
Biso mean---25.74 -
Num. residues----99
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.014841
X-RAY DIFFRACTIONr_bond_other_d0.0010.017791
X-RAY DIFFRACTIONr_angle_refined_deg1.6421.661134
X-RAY DIFFRACTIONr_angle_other_deg0.9091.6351847
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.579597
X-RAY DIFFRACTIONr_dihedral_angle_2_deg42.36422.61942
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.61815160
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.381154
X-RAY DIFFRACTIONr_chiral_restr0.0860.2105
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.02904
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02160
LS refinement shellResolution: 2.4→2.462 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.369 20 -
Rwork0.215 295 -
all-315 -
obs--95.74 %
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)
10.5286-0.1775-0.39222.64060.8160.9562-0.0478-0.0181-0.00160.03490.0676-0.01680.01260.0238-0.01970.03030.0025-0.01090.0157-0.00010.0065-8.3587-17.76047.764
23.6931-4.8477-2.57089.52215.4423.1440.37010.3187-0.237-0.4152-0.54260.302-0.2112-0.30090.17250.03820.0329-0.01720.0540.01390.0697-9.1632-8.8945-0.3104
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A25 - 109
2X-RAY DIFFRACTION2B1 - 14

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