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- PDB-4umn: Structure of a stapled peptide antagonist bound to Nutlin-resista... -

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Entry
Database: PDB / ID: 4umn
TitleStructure of a stapled peptide antagonist bound to Nutlin-resistant Mdm2.
Components
  • E3 ubiquitin-protein ligase Mdm2
  • M06
KeywordsCELL CYCLE
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 / 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 / response to ether / traversing start control point of mitotic cell cycle / 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 / response to iron ion / peroxisome proliferator activated receptor binding / negative regulation of protein processing / response to steroid hormone / SUMO transferase activity / NEDD8 ligase activity / AKT phosphorylates targets in the cytosol / cellular response to peptide hormone stimulus / atrioventricular valve morphogenesis / 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 / negative regulation of DNA damage response, signal transduction by p53 class mediator / response to magnesium ion / ligase activity / protein sumoylation / SUMOylation of transcription factors / protein localization to nucleus / cellular response to actinomycin D / cellular response to UV-C / blood vessel remodeling / cellular response to estrogen stimulus / protein autoubiquitination / ribonucleoprotein complex binding / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / positive regulation of vascular associated smooth muscle cell proliferation / transcription repressor complex / NPAS4 regulates expression of target genes / regulation of heart rate / proteolysis involved in protein catabolic process / positive regulation of mitotic cell cycle / positive regulation of protein export from nucleus / response to cocaine / ubiquitin binding / Stabilization of p53 / Regulation of RUNX3 expression and activity / protein destabilization / cellular response to gamma radiation / RING-type E3 ubiquitin transferase / establishment of protein localization / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / response to toxic substance / cellular response to hydrogen peroxide / cellular response to growth factor stimulus / protein polyubiquitination / ubiquitin-protein transferase activity / endocytic vesicle membrane / ubiquitin protein ligase activity / disordered domain specific binding / Regulation of TP53 Degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / p53 binding / negative regulation of neuron projection development / 5S rRNA binding / ubiquitin-dependent protein catabolic process / cellular response to hypoxia / regulation of gene expression / proteasome-mediated ubiquitin-dependent protein catabolic process / protein-containing complex assembly / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / protein ubiquitination / regulation of cell cycle / Ub-specific processing proteases / 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 / negative regulation of transcription by RNA polymerase II / enzyme binding / protein-containing complex / zinc ion binding / nucleoplasm / identical protein binding
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: 1.99 Å
AuthorsChee, S. / Wongsantichon, J. / Quah, S. / Robinson, R.C. / Verma, C. / Lane, D.P. / Brown, C.J. / Ghadessy, F.J.
CitationJournal: PLoS ONE / Year: 2014
Title: Structure of a stapled peptide antagonist bound to nutlin-resistant Mdm2.
Authors: Chee, S.M. / Wongsantichon, J. / Soo Tng, Q. / Robinson, R. / Joseph, T.L. / Verma, C. / Lane, D.P. / Brown, C.J. / Ghadessy, F.J.
History
DepositionMay 20, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 28, 2014Provider: repository / Type: Initial release
Revision 1.1Jul 16, 2014Group: Atomic model / Other
Revision 1.2Aug 27, 2014Group: Database references
Revision 1.3Aug 9, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.page_first ..._citation.journal_abbrev / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _citation_author.name
Revision 1.4Oct 16, 2019Group: Data collection / Derived calculations ...Data collection / Derived calculations / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_status ...exptl_crystal_grow / pdbx_database_status / reflns / reflns_shell / struct_conn
Item: _exptl_crystal_grow.method / _exptl_crystal_grow.temp ..._exptl_crystal_grow.method / _exptl_crystal_grow.temp / _pdbx_database_status.status_code_sf / _reflns.pdbx_Rmerge_I_obs / _reflns_shell.Rmerge_I_obs / _struct_conn.pdbx_leaving_atom_flag
Revision 2.0Mar 15, 2023Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / chem_comp / database_2 / entity / entity_name_com / entity_poly / entity_poly_seq / entity_src_gen / pdbx_entity_src_syn / pdbx_poly_seq_scheme / struct_conn / struct_ref / struct_ref_seq / struct_ref_seq_dif
Item: _atom_site.auth_comp_id / _atom_site.label_comp_id ..._atom_site.auth_comp_id / _atom_site.label_comp_id / _atom_site_anisotrop.pdbx_auth_comp_id / _atom_site_anisotrop.pdbx_label_comp_id / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_ec / _entity_name_com.name / _entity_poly.pdbx_seq_one_letter_code / _entity_poly_seq.mon_id / _entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_beg_seq_num / _entity_src_gen.pdbx_end_seq_num / _entity_src_gen.pdbx_gene_src_gene / _entity_src_gen.pdbx_gene_src_scientific_name / _entity_src_gen.pdbx_seq_type / _pdbx_entity_src_syn.pdbx_beg_seq_num / _pdbx_entity_src_syn.pdbx_end_seq_num / _pdbx_poly_seq_scheme.mon_id / _pdbx_poly_seq_scheme.pdb_mon_id / _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_ref.pdbx_align_begin / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.db_align_beg / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_auth_seq_align_beg / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_ref_seq.seq_align_beg / _struct_ref_seq.seq_align_end / _struct_ref_seq_dif.details
Revision 3.0Nov 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 / 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 / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_label_atom_id
Revision 3.1Feb 7, 2024Group: 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: E3 ubiquitin-protein ligase Mdm2
B: E3 ubiquitin-protein ligase Mdm2
C: M06
D: M06


Theoretical massNumber of molelcules
Total (without water)30,1554
Polymers30,1554
Non-polymers00
Water1,53185
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5560 Å2
ΔGint-22.6 kcal/mol
Surface area9650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.076, 65.674, 105.683
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP22121

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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: 13535.410 Da / Num. of mol.: 2 / Fragment: P53 BINDING DOMAIN, RESIDUES 6-125 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Plasmid: PGEX-6-P-1(MDM2-6-125) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: Q00987, RING-type E3 ubiquitin transferase
#2: Protein/peptide M06


Mass: 1541.850 Da / Num. of mol.: 2 / Fragment: MDM2 INTERACTING PEPTIDE, RESIDUES 17-27 / Source method: obtained synthetically / Source: (synth.) SYNTHETIC CONSTRUCT (others)
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 85 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsMETHYLAMINE (NME): AMIDATION OF C-TERMINAL RESIDUE IN CHAINS C AND D.

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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: 2.42 Å3/Da / Density % sol: 49.24 % / Description: NONE
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 6.4
Details: 0.04 M CITRIC ACID, 0.06 M BIS-TRIS PROPANE PH 6.4, AND 20% PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Type: NSRRC / Wavelength: 1
DetectorDate: Apr 7, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.97→30 Å / Num. obs: 19576 / % possible obs: 99.3 % / Observed criterion σ(I): 2 / Redundancy: 6.4 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 34.74
Reflection shellResolution: 1.97→2.02 Å / Redundancy: 5.8 % / Rmerge(I) obs: 0.34 / Mean I/σ(I) obs: 4.87 / % possible all: 95.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0069refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2AXI

2axi


Resolution: 1.99→105.68 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.926 / SU B: 8.541 / SU ML: 0.118 / Cross valid method: THROUGHOUT / ESU R: 0.169 / ESU R Free: 0.153 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.23683 1011 5.3 %RANDOM
Rwork0.20049 ---
obs0.2023 18187 99.17 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 34.247 Å2
Baniso -1Baniso -2Baniso -3
1--1.27 Å20 Å20 Å2
2--0.91 Å20 Å2
3---0.36 Å2
Refinement stepCycle: LAST / Resolution: 1.99→105.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1757 0 0 85 1842
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.021806
X-RAY DIFFRACTIONr_bond_other_d0.0010.021802
X-RAY DIFFRACTIONr_angle_refined_deg1.262.022428
X-RAY DIFFRACTIONr_angle_other_deg1.08734136
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3985200
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.76223.50677
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.64815324
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.024159
X-RAY DIFFRACTIONr_chiral_restr0.0530.2273
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0211910
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02413
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_it0.3511.668838
X-RAY DIFFRACTIONr_mcbond_other0.3521.669832
X-RAY DIFFRACTIONr_mcangle_it0.6042.5071023
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.3531.708968
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_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.99→2.042 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.279 69 -
Rwork0.249 1240 -
obs--92.05 %
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)
18.62954.358-2.24669.2044-0.61273.93060.05220.11040.3432-0.477-0.2466-0.0645-0.074-0.13650.19440.37860.0631-0.04690.11430.02270.06674.0423.7613111.8238
21.383-1.28570.07874.6729-1.72244.20310.05090.0577-0.098-0.3774-0.1643-0.19490.07530.15080.11350.170.0211-0.02770.0251-0.0030.05117.517514.9838119.5812
33.3358-0.81230.34535.1555-0.33851.9698-0.0059-0.3026-0.25150.3811-0.03750.4489-0.0523-0.07530.04340.12130.01930.00550.06880.00160.1187-8.258622.7696135.972
410.53222.8638-5.835610.1356-2.91387.11140.57180.27611.48271.52850.77952.7956-0.9869-1.0337-1.35130.37550.25730.36490.24620.22170.941-8.258622.7696135.972
54.7983-3.9963-6.15818.1199.190111.3599-1.2606-0.3114-0.81612.0931-0.00850.91342.50980.20951.26910.71380.05580.2160.09710.10730.2685-8.258622.7696135.972
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A18 - 48
2X-RAY DIFFRACTION2A49 - 112
3X-RAY DIFFRACTION3B18 - 110
4X-RAY DIFFRACTION4C17 - 28
5X-RAY DIFFRACTION5D17 - 28

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