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- PDB-3tpx: Crystal structure of human MDM2 in complex with a trifluoromethyl... -

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Basic information

Entry
Database: PDB / ID: 3tpx
TitleCrystal structure of human MDM2 in complex with a trifluoromethylated D-peptide inhibitor
Components
  • D-peptide inhibitor DPMI-delta
  • E3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE/LIGASE INHIBITOR / LIGASE-LIGASE INHIBITOR complex / MDM2-D-peptide inhibitor complex / p53-binding domain of MDM2-D-peptide 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 / 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 / response to toxic substance / cellular response to gamma radiation / 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 / p53 binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / negative regulation of neuron projection development / cellular response to hypoxia / 5S rRNA binding / 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
D-peptide inhibitor DPMI-delta / ACETATE ION / polypeptide(D) / polypeptide(D) (> 10) / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsWu, X. / Pazgier, M.
CitationJournal: J.Med.Chem. / Year: 2012
Title: An Ultrahigh Affinity d-Peptide Antagonist Of MDM2.
Authors: Zhan, C. / Zhao, L. / Wei, X. / Wu, X. / Chen, X. / Yuan, W. / Lu, W.Y. / Pazgier, M. / Lu, W.
History
DepositionSep 8, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 20, 2012Provider: repository / Type: Initial release
Revision 1.1Jun 27, 2012Group: Database references
Revision 1.2Jul 25, 2012Group: Database references
Revision 1.3Dec 12, 2012Group: Other
Revision 1.4Jun 19, 2013Group: Structure summary
Revision 1.5Sep 13, 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 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.6Dec 6, 2023Group: Data collection / Derived calculations / Category: chem_comp_atom / chem_comp_bond / struct_conn
Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2 / _struct_conn.pdbx_leaving_atom_flag

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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: D-peptide inhibitor DPMI-delta
C: E3 ubiquitin-protein ligase Mdm2
D: D-peptide inhibitor DPMI-delta
E: E3 ubiquitin-protein ligase Mdm2
F: D-peptide inhibitor DPMI-delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,57818
Polymers34,8776
Non-polymers70212
Water4,053225
1
A: E3 ubiquitin-protein ligase Mdm2
B: D-peptide inhibitor DPMI-delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,7223
Polymers11,6262
Non-polymers961
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1660 Å2
ΔGint-21 kcal/mol
Surface area5890 Å2
MethodPISA
2
C: E3 ubiquitin-protein ligase Mdm2
D: D-peptide inhibitor DPMI-delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,0669
Polymers11,6262
Non-polymers4407
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1920 Å2
ΔGint-29 kcal/mol
Surface area5670 Å2
MethodPISA
3
E: E3 ubiquitin-protein ligase Mdm2
F: D-peptide inhibitor DPMI-delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,7916
Polymers11,6262
Non-polymers1654
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1640 Å2
ΔGint-30 kcal/mol
Surface area5950 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.532, 211.811, 45.327
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-392-

HOH

21C-346-

HOH

31E-351-

HOH

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Components

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Protein / Polypeptide(D) , 2 types, 6 molecules ACEBDF

#1: Protein E3 ubiquitin-protein ligase Mdm2 / Double minute 2 protein / Hdm2 / Oncoprotein Mdm2 / p53-binding protein Mdm2


Mass: 10044.889 Da / Num. of mol.: 3 / Fragment: p53 binding domain (UNP residues 25-109) / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: Q00987, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Polypeptide(D) D-peptide inhibitor DPMI-delta


Type: Peptide-like / Class: Inhibitor / Mass: 1580.729 Da / Num. of mol.: 3 / Source method: obtained synthetically / References: D-peptide inhibitor DPMI-delta

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Non-polymers , 4 types, 237 molecules

#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Cl
#5: Chemical
ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H3O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 225 / Source method: isolated from a natural source / Formula: H2O

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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: 2.43 Å3/Da / Density % sol: 49.32 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 0.1 M MES, pH 5.5, 25% PEG4000, 0.15 M ammonium sulfate, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 29, 2011
RadiationMonochromator: side scattering I-beam bent single crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.75→50 Å / Num. all: 34913 / Num. obs: 34765 / % possible obs: 58.9 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 6.5 % / Rmerge(I) obs: 0.048 / Rsym value: 0.04 / Net I/σ(I): 40.8
Reflection shellResolution: 1.75→1.78 Å / Redundancy: 6.6 % / Rmerge(I) obs: 0.781 / Mean I/σ(I) obs: 2 / % possible all: 99.9

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
REFMAC5.5.0109refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3LNJ

3lnj


Resolution: 1.8→20 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.946 / SU B: 5.066 / SU ML: 0.092 / Cross valid method: THROUGHOUT / ESU R: 0.134 / ESU R Free: 0.126 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.23118 1585 5 %RANDOM
Rwork0.19769 ---
obs0.19942 30272 99.43 %-
all-30272 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 40.58 Å2
Baniso -1Baniso -2Baniso -3
1-0.39 Å20 Å20 Å2
2--0.06 Å20 Å2
3----0.45 Å2
Refinement stepCycle: LAST / Resolution: 1.8→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2398 0 36 225 2659
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0222478
X-RAY DIFFRACTIONr_angle_refined_deg1.6852.0913301
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.835257
X-RAY DIFFRACTIONr_dihedral_angle_2_deg43.31923.11190
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.34315428
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.1681512
X-RAY DIFFRACTIONr_chiral_restr0.1240.2372
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211706
X-RAY DIFFRACTIONr_mcbond_it1.6881.51414
X-RAY DIFFRACTIONr_mcangle_it2.95322246
X-RAY DIFFRACTIONr_scbond_it5.07731064
X-RAY DIFFRACTIONr_scangle_it6.3324.51054
LS refinement shellResolution: 1.8→1.846 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.305 113 -
Rwork0.252 2172 -
obs--99.65 %
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)
10.8644-0.2780.64351.17420.08760.5798-0.09020.13090.06840.14260.0386-0.0733-0.02410.07620.05160.0574-0.0324-0.03150.14330.01140.081122.6911-47.13945.9224
20.42020.07030.27891.3255-0.53691.5794-0.0174-0.05440.0314-0.16080.1330.0702-0.1215-0.2413-0.11550.1219-0.001-0.07180.09550.04990.11269.6377-28.4365-3.2556
30.8253-0.180.10691.3871-0.06630.46970.07030.0195-0.03020.28220.0128-0.1816-0.02530.0106-0.08310.1283-0.0155-0.07110.0130.02430.127120.2131-9.2757.8303
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A26 - 109
2X-RAY DIFFRACTION2C26 - 108
3X-RAY DIFFRACTION3E25 - 108

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