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- PDB-3iwy: Crystal structure of human MDM2 complexed with D-peptide (12 residues) -

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Basic information

Entry
Database: PDB / ID: 3iwy
TitleCrystal structure of human MDM2 complexed with D-peptide (12 residues)
Components
  • D-peptide inhibitor
  • E3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE/LIGASE INHIBITOR / MDM2 / p53 binding domain / D-peptide activator of p53 / Host-virus interaction / Ligase / Metal-binding / Nucleus / Phosphoprotein / Proto-oncogene / Ubl conjugation pathway / Zinc-finger / LIGASE-LIGASE INHIBITOR COMPLEX
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
D-peptide inhibitor / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.93 Å
AuthorsPazgier, M. / Lu, W.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2010
Title: D-peptide inhibitors of the p53-MDM2 interaction for targeted molecular therapy of malignant neoplasms.
Authors: Liu, M. / Li, C. / Pazgier, M. / Li, C. / Mao, Y. / Lv, Y. / Gu, B. / Wei, G. / Yuan, W. / Zhan, C. / Lu, W.Y. / Lu, W.
History
DepositionSep 3, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 21, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Dec 12, 2012Group: Other
Revision 1.3Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag
Revision 1.4Nov 22, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.5Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: D-peptide inhibitor
D: D-peptide inhibitor
A: E3 ubiquitin-protein ligase Mdm2
C: E3 ubiquitin-protein ligase Mdm2


Theoretical massNumber of molelcules
Total (without water)23,1254
Polymers23,1254
Non-polymers00
Water1,910106
1
B: D-peptide inhibitor
A: E3 ubiquitin-protein ligase Mdm2


Theoretical massNumber of molelcules
Total (without water)11,5632
Polymers11,5632
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1110 Å2
ΔGint-13 kcal/mol
Surface area5820 Å2
MethodPISA
2
D: D-peptide inhibitor
C: E3 ubiquitin-protein ligase Mdm2


Theoretical massNumber of molelcules
Total (without water)11,5632
Polymers11,5632
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1110 Å2
ΔGint-13 kcal/mol
Surface area5940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)33.569, 46.503, 49.353
Angle α, β, γ (deg.)90.00, 92.35, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein/peptide D-peptide inhibitor


Type: Peptide-like / Class: Inhibitor / Mass: 1517.748 Da / Num. of mol.: 2 / Source method: obtained synthetically
Details: Synthetic peptide, sequence found by phage display screening
References: D-peptide inhibitor
#2: Protein E3 ubiquitin-protein ligase Mdm2 / p53-binding protein Mdm2 / Oncoprotein Mdm2 / Double minute 2 protein / Hdm2


Mass: 10044.889 Da / Num. of mol.: 2 / Fragment: UNP residues 25-109, SWIB domain / Source method: obtained synthetically / Details: MDM2 sequence accurs naturally in humans
References: UniProt: Q00987, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 106 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationN

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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

Crystal growTemperature: 273 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.05 M potassium phosphate monobasic, 20% PEG 8,000, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 273K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Feb 24, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.93→28.28 Å / Num. all: 11675 / Num. obs: 11041 / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3 % / Rmerge(I) obs: 0.117 / Net I/σ(I): 10.8
Reflection shellResolution: 1.93→1.96 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.471 / Mean I/σ(I) obs: 1.9 / % possible all: 90.3

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
REFMAC5.5.0070refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3EQS

3eqs


Resolution: 1.93→20 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.91 / SU B: 6.074 / SU ML: 0.145 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.284 / ESU R Free: 0.207 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.25856 522 4.7 %RANDOM
Rwork0.2103 ---
obs0.21258 10509 94.56 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.848 Å2
Baniso -1Baniso -2Baniso -3
1-0.11 Å20 Å2-0.1 Å2
2---0.39 Å20 Å2
3---0.27 Å2
Refinement stepCycle: LAST / Resolution: 1.93→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1589 0 0 106 1695
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0221636
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.8992.0222211
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8115187
X-RAY DIFFRACTIONr_dihedral_angle_2_deg43.25323.10358
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.04515286
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.037158
X-RAY DIFFRACTIONr_chiral_restr0.3860.2245
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211198
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_it0.9521.5951
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.51721544
X-RAY DIFFRACTIONr_scbond_it2.6543685
X-RAY DIFFRACTIONr_scangle_it4.0564.5667
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.925→1.975 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3 33 -
Rwork0.245 740 -
obs--87.54 %
Refinement TLS params.Method: refined / Origin x: 9.0588 Å / Origin y: -9.6162 Å / Origin z: 24.0239 Å
111213212223313233
T0.0053 Å2-0.0016 Å2-0.0011 Å2-0.0495 Å2-0.0011 Å2--0.005 Å2
L0.0852 °2-0.0039 °2-0.0398 °2-0.4363 °2-0.008 °2--0.2599 °2
S-0.019 Å °0.0008 Å °0.0089 Å °0.0198 Å °0.0078 Å °0.0348 Å °-0.0028 Å °-0.0191 Å °0.0112 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A26 - 107
2X-RAY DIFFRACTION1A1 - 148

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