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- PDB-4ud7: Structure of the stapled peptide YS-02 bound to MDM2 -

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Basic information

Entry
Database: PDB / ID: 4ud7
TitleStructure of the stapled peptide YS-02 bound to MDM2
Components
  • MDM2
  • YS-02
KeywordsLYASE / MDM2 / STAPLED PEPTIDE / P53
Function / homology
Function and homology information


cellular response to vitamin B1 / response to formaldehyde / response to water-immersion restraint stress / cellular response to UV-C / response to ether / fibroblast activation / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / Trafficking of AMPA receptors / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / receptor serine/threonine kinase binding ...cellular response to vitamin B1 / response to formaldehyde / response to water-immersion restraint stress / cellular response to UV-C / response to ether / fibroblast activation / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / Trafficking of AMPA receptors / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / receptor serine/threonine kinase binding / cellular response to alkaloid / response to steroid hormone / SUMO transferase activity / negative regulation of protein processing / peroxisome proliferator activated receptor binding / positive regulation of vascular associated smooth muscle cell migration / AKT phosphorylates targets in the cytosol / response to iron ion / NEDD8 ligase activity / regulation of protein catabolic process / positive regulation of muscle cell differentiation / cellular response to peptide hormone stimulus / cellular response to antibiotic / regulation of postsynaptic neurotransmitter receptor internalization / SUMOylation of ubiquitinylation proteins / 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 / negative regulation of signal transduction by p53 class mediator / cellular response to estrogen stimulus / protein localization to nucleus / protein sumoylation / response to magnesium ion / ribonucleoprotein complex binding / positive regulation of vascular associated smooth muscle cell proliferation / protein autoubiquitination / positive regulation of mitotic cell cycle / positive regulation of protein export from nucleus / NPAS4 regulates expression of target genes / DNA damage response, signal transduction by p53 class mediator / : / response to cocaine / negative regulation of neuron projection development / cellular response to gamma radiation / establishment of protein localization / ubiquitin binding / Stabilization of p53 / protein destabilization / Regulation of RUNX3 expression and activity / cellular response to growth factor stimulus / response to toxic substance / RING-type E3 ubiquitin transferase / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / Degradation of CDH1 / cellular response to hydrogen peroxide / protein polyubiquitination / disordered domain specific binding / p53 binding / ubiquitin-protein transferase activity / endocytic vesicle membrane / Signaling by ALK fusions and activated point mutants / Regulation of TP53 Degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / ubiquitin protein ligase activity / protein-containing complex assembly / 5S rRNA binding / cellular response to hypoxia / ubiquitin-dependent protein catabolic process / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of cell cycle / postsynaptic density / response to xenobiotic stimulus / protein ubiquitination / Ub-specific processing proteases / protein domain specific binding / response to antibiotic / negative regulation of DNA-templated transcription / ubiquitin protein ligase binding / apoptotic process / positive regulation of gene expression / positive regulation of cell population proliferation / negative regulation of apoptotic process / nucleolus / negative regulation of transcription by RNA polymerase II / glutamatergic synapse / enzyme binding / protein-containing complex / nucleoplasm / zinc ion binding / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
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)
SYNTHETIC CONSTRUCT (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 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 8, 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: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_validate_polymer_linkage / struct_conn / struct_ncs_dom_lim
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 / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 2.0Nov 15, 2023Group: Advisory / Atomic model ...Advisory / 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_polymer_linkage / pdbx_validate_rmsd_angle / 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

Downloads & links

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Assembly

Deposited unit
A: MDM2
B: MDM2
C: MDM2
D: MDM2
F: YS-02
G: YS-02
H: YS-02
I: YS-02


Theoretical massNumber of molelcules
Total (without water)58,6838
Polymers58,6838
Non-polymers00
Water4,720262
1
C: MDM2
H: YS-02


Theoretical massNumber of molelcules
Total (without water)14,6712
Polymers14,6712
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1210 Å2
ΔGint-12.2 kcal/mol
Surface area6380 Å2
MethodPISA
2
D: MDM2
I: YS-02


Theoretical massNumber of molelcules
Total (without water)14,6712
Polymers14,6712
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1030 Å2
ΔGint-10.4 kcal/mol
Surface area6310 Å2
MethodPISA
3
B: MDM2
G: YS-02


Theoretical massNumber of molelcules
Total (without water)14,6712
Polymers14,6712
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1510 Å2
ΔGint-14.5 kcal/mol
Surface area6890 Å2
MethodPISA
4
A: MDM2
F: YS-02


Theoretical massNumber of molelcules
Total (without water)14,6712
Polymers14,6712
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1400 Å2
ΔGint-14 kcal/mol
Surface area7110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.148, 69.538, 78.464
Angle α, β, γ (deg.)90.00, 102.36, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails (eV)
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: _ / Beg auth comp-ID: SER / Beg label comp-ID: SER / Refine code: _

Dom-IDEns-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11VALVALAA16 - 1105 - 99
21VALVALBB16 - 1105 - 99
12VALVALAA17 - 1106 - 99
22VALVALCC17 - 1106 - 99
13VALVALAA17 - 1106 - 99
23VALVALDD17 - 1106 - 99
14VALVALBB17 - 1106 - 99
24VALVALCC17 - 1106 - 99
15VALVALBB17 - 1106 - 99
25VALVALDD17 - 1106 - 99
16GLNGLNCC17 - 1126 - 101
26GLNGLNDD17 - 1126 - 101

NCS ensembles :
ID
1
2
3
4
5
6

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Components

#1: Protein
MDM2


Mass: 12830.667 Da / Num. of mol.: 4 / Fragment: P53 BINDING DOMAIN, UNP RESIDUES 17-125 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PGEX6P-1 / 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-02


Mass: 1840.102 Da / Num. of mol.: 4 / Source method: obtained synthetically
Details: STAPLED PEPTIDE, COVALENT BOND BETWEEN THE SIDE CHAINS OF RESIDUES 20 AND 24.
Source: (synth.) SYNTHETIC CONSTRUCT (others)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 262 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsAMINO GROUP (NH2): STAPLED PEPTIDE IS AMIDATED AT THE C-TERMINUS. ACETYL GROUP (ACE): STAPLED ...AMINO GROUP (NH2): STAPLED PEPTIDE IS AMIDATED AT THE C-TERMINUS. ACETYL GROUP (ACE): STAPLED PEPTIDE IS ACETYLATED AT THE N-TERMINUS. 2 (R)-2-(4'-PENTENYL)ALANINE (2JN): THIS NON-NATURAL AMINO ACID FORMS A COVALENT BOND BETWEEN RESIDUES 20 AND 24
Sequence detailsE69 AND K70 ARE MUTATED TO ALANINES FOR SURFACE ENTROPY REDUCTION. THE GPLGS OF THE CRYSTALLISATION ...E69 AND K70 ARE MUTATED TO ALANINES FOR SURFACE ENTROPY REDUCTION. THE GPLGS 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.

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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 / Details: 0.1 M SODIUM CITRATE PH 4.0 AND 15 % PEG8000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 3, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 1.6→52 Å / Num. obs: 62522 / % possible obs: 97.9 % / Observed criterion σ(I): 1.9 / Redundancy: 3.7 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 12.1
Reflection shellResolution: 1.6→1.63 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.69 / Mean I/σ(I) obs: 1.9 / % possible all: 93.9

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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: 1.6→76.65 Å / Cor.coef. Fo:Fc: 0.977 / Cor.coef. Fo:Fc free: 0.967 / SU B: 3.544 / SU ML: 0.054 / Cross valid method: THROUGHOUT / ESU R: 0.094 / ESU R Free: 0.076 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.17838 3198 5.1 %RANDOM
Rwork0.13846 ---
obs0.1405 59304 97.71 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 23.018 Å2
Baniso -1Baniso -2Baniso -3
1--1.06 Å20 Å20 Å2
2--0.36 Å20 Å2
3---0.64 Å2
Refinement stepCycle: LAST / Resolution: 1.6→76.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3577 0 0 262 3839
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.023831
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4782.0015203
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5725455
X-RAY DIFFRACTIONr_dihedral_angle_2_deg44.53624.051158
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.16315694
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.3341516
X-RAY DIFFRACTIONr_chiral_restr0.0920.2594
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212792
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_it2.691.8421828
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it3.3272.752281
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it4.5232.3732003
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined5.31417.1186017
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr3.65533831
X-RAY DIFFRACTIONr_sphericity_free27.8795116
X-RAY DIFFRACTIONr_sphericity_bonded15.1453892
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A1170.11
12B1170.11
21A1040.22
22C1040.22
31A920.2
32D920.2
41B1100.24
42C1100.24
51B970.23
52D970.23
61C1120.14
62D1120.14
LS refinement shellResolution: 1.6→1.642 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.26 221 -
Rwork0.219 4258 -
obs--95.14 %

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