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- PDB-6t2d: Multicomponent Peptide Stapling as a Diversity-Driven Tool for th... -

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Basic information

Entry
Database: PDB / ID: 6t2d
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-Gp
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 / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / response to ether / 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 / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / response to ether / 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 / AKT phosphorylates targets in the cytosol / atrioventricular valve morphogenesis / cellular response to peptide hormone stimulus / ventricular septum development / endocardial cushion morphogenesis / positive regulation of muscle cell differentiation / SUMOylation of ubiquitinylation proteins / cellular response to alkaloid / blood vessel development / regulation of protein catabolic process / cardiac septum morphogenesis / Constitutive Signaling by AKT1 E17K in Cancer / ligase activity / negative regulation of DNA damage response, signal transduction by p53 class mediator / response to magnesium ion / SUMOylation of transcription factors / 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 / NPAS4 regulates expression of target genes / transcription repressor complex / regulation of heart rate / positive regulation of mitotic cell cycle / positive regulation of protein export from nucleus / response to cocaine / proteolysis involved in protein catabolic process / ubiquitin binding / Stabilization of p53 / Regulation of RUNX3 expression and activity / protein destabilization / RING-type E3 ubiquitin transferase / establishment of protein localization / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / cellular response to gamma radiation / response to toxic substance / cellular response to growth factor stimulus / cellular response to hydrogen peroxide / protein polyubiquitination / ubiquitin-protein transferase activity / endocytic vesicle membrane / ubiquitin protein ligase activity / disordered domain specific binding / Signaling by ALK fusions and activated point mutants / Regulation of TP53 Degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / p53 binding / negative regulation of neuron projection development / 5S rRNA binding / cellular response to hypoxia / ubiquitin-dependent protein catabolic process / regulation of gene expression / protein-containing complex assembly / proteasome-mediated ubiquitin-dependent protein catabolic process / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / Ub-specific processing proteases / regulation of cell cycle / protein ubiquitination / response to xenobiotic stimulus / protein domain specific binding / response to antibiotic / negative regulation of DNA-templated transcription / apoptotic process / ubiquitin protein ligase binding / positive regulation of cell population proliferation / positive regulation of gene expression / nucleolus / negative regulation of apoptotic process / enzyme binding / negative regulation of transcription by RNA polymerase II / 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
Chem-M9E / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 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-Gp
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,4445
Polymers11,8492
Non-polymers5953
Water2,234124
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: MST, Microscale Thermophoresis
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1900 Å2
ΔGint-9 kcal/mol
Surface area6580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.017, 41.017, 104.995
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121
Components on special symmetry positions
IDModelComponents
11A-397-

HOH

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AB

#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 / Plasmid: pETM13 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q00987, RING-type E3 ubiquitin transferase
#2: Protein/peptide Stapled peptide GAR300-Gp


Mass: 1656.789 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 4 types, 127 molecules

#3: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-M9E / 2-(methylamino)-~{N}-[[4-[[2-(methylamino)ethanoylamino]methyl]phenyl]methyl]ethanamide


Mass: 278.350 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H22N4O2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 124 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.15 Å3/Da / Density % sol: 42.84 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.1M TRIS pH 8, 0.2M Ammonium Sulfate, 30% PEG-3350

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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: Apr 8, 2018 / Details: double crystal monochromator
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 1.65→35.52 Å / Num. obs: 12894 / % possible obs: 99.7 % / Redundancy: 8.9 % / CC1/2: 0.999 / Rmerge(I) obs: 0.068 / Rpim(I) all: 0.024 / Rrim(I) all: 0.073 / Net I/σ(I): 18.1 / Num. measured all: 114541
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.65-1.687.40.8035800.8990.3020.8695.3
9.05-35.527.10.0461070.9980.0170.04998.8

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Processing

Software
NameVersionClassification
REFMACrefmac_5.8.0230refinement
XDSdata reduction
Aimless0.6.3data scaling
PDB_EXTRACT3.25data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1rv1

1rv1


Resolution: 1.8→35.52 Å / Cor.coef. Fo:Fc: 0.972 / Cor.coef. Fo:Fc free: 0.934 / SU B: 6.646 / SU ML: 0.092 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.37 / ESU R Free: 0.134
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2257 451 4.5 %RANDOM
Rwork0.1323 ---
obs0.1364 9597 99.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 188.72 Å2 / Biso mean: 20.772 Å2 / Biso min: 8.21 Å2
Baniso -1Baniso -2Baniso -3
1--0.1 Å2-0.05 Å20 Å2
2---0.1 Å20 Å2
3---0.31 Å2
Refinement stepCycle: final / Resolution: 1.8→35.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms823 0 39 124 986
Biso mean--61.57 34.83 -
Num. residues----99
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0250.014917
X-RAY DIFFRACTIONr_bond_other_d0.0020.017867
X-RAY DIFFRACTIONr_angle_refined_deg1.9931.6911235
X-RAY DIFFRACTIONr_angle_other_deg0.9571.6712029
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1545106
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.52422.22245
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.93215170
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.776154
X-RAY DIFFRACTIONr_chiral_restr0.0950.2115
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.02978
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02174
X-RAY DIFFRACTIONr_rigid_bond_restr3.16231779
X-RAY DIFFRACTIONr_sphericity_free30.52595
X-RAY DIFFRACTIONr_sphericity_bonded20.75551790
LS refinement shellResolution: 1.8→1.847 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.33 36 -
Rwork0.173 689 -
all-725 -
obs--100 %
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)
10.04810.01130.03230.08910.00860.086-0.0022-0.0066-0.0019-0.00220.0040.0029-0.0022-0.0045-0.00180.0060.001400.00740.00020.0002-0.178516.4365-9.0204
243.9033-4.03233.86930.3714-0.35580.3413-0.03280.36250.8726-0.0014-0.0356-0.0696-0.00050.03070.06840.0512-0.0133-0.05410.05540.06780.2047-8.761330.6703-14.1553
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A25 - 109
2X-RAY DIFFRACTION2B1

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