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- PDB-4ue1: Structure of the stapled peptide YS-01 bound to MDM2 -

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Basic information

Entry
Database: PDB / ID: 4ue1
TitleStructure of the stapled peptide YS-01 bound to MDM2
Components
  • E3 UBIQUITIN-PROTEIN LIGASE MDM2
  • YS-01
KeywordsLIGASE/PEPTIDE / LIGASE-PEPTIDE COMPLEX
Function / homology
Function and homology information


cellular response to vitamin B1 / response to formaldehyde / response to water-immersion restraint stress / response to ether / traversing start control point of mitotic cell cycle / atrial septum development / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / fibroblast activation / Trafficking of AMPA receptors / receptor serine/threonine kinase binding ...cellular response to vitamin B1 / response to formaldehyde / response to water-immersion restraint stress / response to ether / traversing start control point of mitotic cell cycle / atrial septum development / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / fibroblast activation / Trafficking of AMPA receptors / receptor serine/threonine kinase binding / peroxisome proliferator activated receptor binding / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / positive regulation of vascular associated smooth muscle cell migration / negative regulation of protein processing / SUMO transferase activity / response to steroid hormone / NEDD8 ligase activity / AKT phosphorylates targets in the cytosol / response to iron ion / atrioventricular valve morphogenesis / endocardial cushion morphogenesis / cellular response to peptide hormone stimulus / ventricular septum development / positive regulation of muscle cell differentiation / cardiac septum morphogenesis / regulation of postsynaptic neurotransmitter receptor internalization / blood vessel development / SUMOylation of ubiquitinylation proteins / ligase activity / cellular response to alkaloid / Constitutive Signaling by AKT1 E17K in Cancer / regulation of protein catabolic process / negative regulation of signal transduction by p53 class mediator / negative regulation of DNA damage response, signal transduction by p53 class mediator / SUMOylation of transcription factors / response to magnesium ion / cellular response to UV-C / protein sumoylation / cellular response to actinomycin D / blood vessel remodeling / cellular response to estrogen stimulus / protein localization to nucleus / ribonucleoprotein complex binding / protein autoubiquitination / positive regulation of vascular associated smooth muscle cell proliferation / NPAS4 regulates expression of target genes / transcription repressor complex / positive regulation of mitotic cell cycle / regulation of heart rate / proteolysis involved in protein catabolic process / positive regulation of protein export from nucleus / ubiquitin binding / response to cocaine / DNA damage response, signal transduction by p53 class mediator / Stabilization of p53 / establishment of protein localization / Regulation of RUNX3 expression and activity / cellular response to gamma radiation / Oncogene Induced Senescence / RING-type E3 ubiquitin transferase / protein destabilization / Regulation of TP53 Activity through Methylation / cellular response to growth factor stimulus / response to toxic substance / centriolar satellite / cellular response to hydrogen peroxide / protein polyubiquitination / ubiquitin-protein transferase activity / disordered domain specific binding / endocytic vesicle membrane / p53 binding / ubiquitin protein ligase activity / Signaling by ALK fusions and activated point mutants / Regulation of TP53 Degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / negative regulation of neuron projection development / 5S rRNA binding / protein-containing complex assembly / ubiquitin-dependent protein catabolic process / Oxidative Stress Induced Senescence / cellular response to hypoxia / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of cell cycle / Ub-specific processing proteases / postsynaptic density / protein ubiquitination / response to xenobiotic stimulus / protein domain specific binding / response to antibiotic / negative regulation of DNA-templated transcription / positive regulation of cell population proliferation / apoptotic process / ubiquitin protein ligase binding / positive regulation of gene expression / negative regulation of apoptotic process / nucleolus / glutamatergic synapse / enzyme binding
Similarity search - Function
E3 ubiquitin-protein ligase Mdm2 / MDM2, modified RING finger, HC subclass / MDM2 / SWIB/MDM2 domain / 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 ...E3 ubiquitin-protein ligase Mdm2 / MDM2, modified RING finger, HC subclass / MDM2 / SWIB/MDM2 domain / 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 superfamily / Zinc finger RanBP2-type signature. / 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)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.45 Å
AuthorsTan, Y.S. / Reeks, J. / Brown, C.J. / Jennings, C.E. / Eapen, R.S. / Tng, Q.S. / Thean, D. / Ying, Y.T. / Gago, F.J.F. / Lane, D.P. ...Tan, Y.S. / Reeks, J. / Brown, C.J. / Jennings, C.E. / Eapen, R.S. / Tng, Q.S. / Thean, D. / Ying, Y.T. / Gago, F.J.F. / Lane, D.P. / Noble, M.E.M. / Verma, C.
CitationJournal: J Phys Chem Lett / Year: 2016
Title: Benzene Probes in Molecular Dynamics Simulations Reveal Novel Binding Sites for Ligand Design.
Authors: Tan, Y.S. / Reeks, J. / Brown, C.J. / Thean, D. / Ferrer Gago, F.J. / Yuen, T.Y. / Goh, E.T. / Lee, X.E. / Jennings, C.E. / Joseph, T.L. / Lakshminarayanan, R. / Lane, D.P. / Noble, M.E. / Verma, C.S.
History
DepositionDec 14, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 13, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 18, 2017Group: Database references
Revision 1.2Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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 2.0Nov 15, 2023Group: Atomic model / Data collection / Derived calculations
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / chem_comp_atom / chem_comp_bond / pdbx_validate_rmsd_bond / struct_conn
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _atom_site_anisotrop.pdbx_auth_atom_id / _atom_site_anisotrop.pdbx_label_atom_id / _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2 / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_label_atom_id
Revision 2.1Dec 20, 2023Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: E3 UBIQUITIN-PROTEIN LIGASE MDM2
B: E3 UBIQUITIN-PROTEIN LIGASE MDM2
C: E3 UBIQUITIN-PROTEIN LIGASE MDM2
D: E3 UBIQUITIN-PROTEIN LIGASE MDM2
F: YS-01
G: YS-01
H: YS-01
I: YS-01


Theoretical massNumber of molelcules
Total (without water)58,6198
Polymers58,6198
Non-polymers00
Water4,810267
1
C: E3 UBIQUITIN-PROTEIN LIGASE MDM2
H: YS-01


Theoretical massNumber of molelcules
Total (without water)14,6552
Polymers14,6552
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1280 Å2
ΔGint-12 kcal/mol
Surface area6330 Å2
MethodPISA
2
D: E3 UBIQUITIN-PROTEIN LIGASE MDM2
I: YS-01


Theoretical massNumber of molelcules
Total (without water)14,6552
Polymers14,6552
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1280 Å2
ΔGint-11.6 kcal/mol
Surface area6240 Å2
MethodPISA
3
A: E3 UBIQUITIN-PROTEIN LIGASE MDM2
F: YS-01


Theoretical massNumber of molelcules
Total (without water)14,6552
Polymers14,6552
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1640 Å2
ΔGint-14.6 kcal/mol
Surface area7290 Å2
MethodPISA
4
B: E3 UBIQUITIN-PROTEIN LIGASE MDM2
G: YS-01


Theoretical massNumber of molelcules
Total (without water)14,6552
Polymers14,6552
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1530 Å2
ΔGint-13.3 kcal/mol
Surface area7190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.104, 69.462, 78.562
Angle α, β, γ (deg.)90.00, 101.96, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
E3 UBIQUITIN-PROTEIN LIGASE MDM2 / DOUBLE MINUTE 2 PROTEIN / HDM2 / ONCOPROTEIN MDM2 / P53-BINDING PROTEIN MDM2 / MDM2


Mass: 12830.667 Da / Num. of mol.: 4 / Fragment: P53 BINDING DOMAIN, RESIDUES 17-125 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): PLYSS
References: UniProt: Q00987, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Protein/peptide
YS-01


Mass: 1824.102 Da / Num. of mol.: 4 / Source method: obtained synthetically
Details: STAPLED PEPTIDE, COVALENT BOND BETWEEN RESIDUES 20 AND 24.
Source: (synth.) HOMO SAPIENS (human)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 267 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer details2-METHYL-D-NORLEUCINE (2JN): RESIDUES 20 AND 24 FORM A COVALENT BOND, THE HYDROCARBON STAPLE. AMINO ...2-METHYL-D-NORLEUCINE (2JN): RESIDUES 20 AND 24 FORM A COVALENT BOND, THE HYDROCARBON STAPLE. AMINO GROUP (NH2): STAPLED PEPTIDE IS AMIDATED AT THE C-TERMINUS. ACETYL GROUP (ACE): STAPLED PEPTIDE IS ACETYLATED AT THE N-TERMINUS.
Sequence detailsE69 AND K70 ARE MUTATED TO ALANINES FOR SURFACE ENTROPY REDUCTION. THE GPLGS AT THE BEGINNING OF ...E69 AND K70 ARE MUTATED TO ALANINES FOR SURFACE ENTROPY REDUCTION. THE GPLGS AT THE BEGINNING OF THE CRYSTALLISATION CONSTRUCT IS AN ARTEFACT OF OUR CLONING AND PURIFICATION STRATEGIES. THIS STAPLED PEPTIDE WAS ORIGINALLY BASED ON A P53 PEPTIDE BUT IS NOW SO HEAVILY MODIFIED SO AS TO BEAR LITTLE RESEMBLANCE TO THE ORIGINAL SEQUENCE. NON-NATURAL AMINO ACIDS ARE USED TO FORM THE HYDROCARBON STAPLE.

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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: 2.8 Å3/Da / Density % sol: 56 % / Description: NONE
Crystal growpH: 4.2
Details: 0.1 M SODIUM CITRATE PH 4.2, 0.2 M SODIUM CHLORIDE AND 20 % PEG8000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.98
DetectorType: DECTRIS PIXEL / Detector: PIXEL / Date: Mar 8, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.45→51.53 Å / Num. obs: 84267 / % possible obs: 98.1 % / Observed criterion σ(I): 1.7 / Redundancy: 3.5 % / Rmerge(I) obs: 0.03 / Net I/σ(I): 16.1
Reflection shellResolution: 1.45→1.47 Å / Redundancy: 2.2 % / Rmerge(I) obs: 0.58 / Mean I/σ(I) obs: 1.7 / % possible all: 84.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1YCR

1ycr


Resolution: 1.45→76.86 Å / Cor.coef. Fo:Fc: 0.976 / Cor.coef. Fo:Fc free: 0.964 / SU B: 2.357 / SU ML: 0.04 / Cross valid method: THROUGHOUT / ESU R: 0.064 / ESU R Free: 0.062 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES REFINED INDIVIDUALLY. NCSR LOCAL WAS USED DURING REFINEMENT.
RfactorNum. reflection% reflectionSelection details
Rfree0.18367 4214 5 %RANDOM
Rwork0.14048 ---
obs0.14262 80031 98.05 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.362 Å2
Baniso -1Baniso -2Baniso -3
1--0.47 Å20 Å20.14 Å2
2--0.2 Å20 Å2
3---0.19 Å2
Refinement stepCycle: LAST / Resolution: 1.45→76.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3627 0 0 267 3894
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0193896
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6042.0055295
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7665467
X-RAY DIFFRACTIONr_dihedral_angle_2_deg43.26624.088159
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.515702
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.3631516
X-RAY DIFFRACTIONr_chiral_restr0.0950.2600
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0212862
X-RAY DIFFRACTIONr_gen_planes_other
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_it2.2291.7381870
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.852.6032338
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.5032.1942026
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr4.15733896
X-RAY DIFFRACTIONr_sphericity_free21.55104
X-RAY DIFFRACTIONr_sphericity_bonded11.4453968
LS refinement shellResolution: 1.45→1.488 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.308 279 -
Rwork0.244 5170 -
obs--85.54 %

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