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- PDB-7bit: Inhibitor of MDM2-p53 Interaction -

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Basic information

Entry
Database: PDB / ID: 7bit
TitleInhibitor of MDM2-p53 Interaction
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsAPOPTOSIS / ligase / cell cycle / protein binding
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
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. ...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
Similarity search - Domain/homology
Chem-TV5 / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.13 Å
AuthorsWilliams, P.A.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein-Protein Interaction.
Authors: Chessari, G. / Hardcastle, I.R. / Ahn, J.S. / Anil, B. / Anscombe, E. / Bawn, R.H. / Bevan, L.D. / Blackburn, T.J. / Buck, I. / Cano, C. / Carbain, B. / Castro, J. / Cons, B. / Cully, S.J. / ...Authors: Chessari, G. / Hardcastle, I.R. / Ahn, J.S. / Anil, B. / Anscombe, E. / Bawn, R.H. / Bevan, L.D. / Blackburn, T.J. / Buck, I. / Cano, C. / Carbain, B. / Castro, J. / Cons, B. / Cully, S.J. / Endicott, J.A. / Fazal, L. / Golding, B.T. / Griffin, R.J. / Haggerty, K. / Harnor, S.J. / Hearn, K. / Hobson, S. / Holvey, R.S. / Howard, S. / Jennings, C.E. / Johnson, C.N. / Lunec, J. / Miller, D.C. / Newell, D.R. / Noble, M.E.M. / Reeks, J. / Revill, C.H. / Riedinger, C. / St Denis, J.D. / Tamanini, E. / Thomas, H. / Thompson, N.T. / Vinkovic, M. / Wedge, S.R. / Williams, P.A. / Wilsher, N.E. / Zhang, B. / Zhao, Y.
History
DepositionJan 13, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 7, 2021Provider: repository / Type: Initial release
Revision 2.0Apr 21, 2021Group: Advisory / Atomic model ...Advisory / Atomic model / Database references / Derived calculations / Experimental preparation / Non-polymer description / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / chem_comp / citation / citation_author / entity / entity_poly / entity_poly_seq / entity_src_gen / exptl_crystal / pdbx_poly_seq_scheme / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_residues / struct_conf / struct_ref / struct_ref_seq / struct_ref_seq_dif / struct_sheet_range / struct_site_gen
Item: _atom_site.label_seq_id / _atom_site_anisotrop.pdbx_label_seq_id ..._atom_site.label_seq_id / _atom_site_anisotrop.pdbx_label_seq_id / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_ec / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _exptl_crystal.density_Matthews / _exptl_crystal.density_percent_sol / _pdbx_struct_sheet_hbond.range_1_label_seq_id / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _struct_conf.beg_label_seq_id / _struct_conf.end_label_seq_id / _struct_sheet_range.beg_label_seq_id / _struct_sheet_range.end_label_seq_id / _struct_site_gen.label_seq_id
Revision 2.1May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,4583
Polymers12,8311
Non-polymers6272
Water1,04558
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area90 Å2
ΔGint-6 kcal/mol
Surface area5730 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.022, 71.022, 101.194
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number179
Space group name H-MP6522

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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: 12830.667 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): pLysS
References: UniProt: Q00987, RING-type E3 ubiquitin transferase
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-TV5 / (3~{R})-2-[(5-chloranylpyridin-2-yl)methyl]-3-(4-chlorophenyl)-4-fluoranyl-3-[(1-oxidanylcyclopropyl)methoxy]-6-(2-oxidanylpropan-2-yl)isoindol-1-one


Mass: 531.403 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H25Cl2FN2O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 58 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.87 Å3/Da / Density % sol: 57.16 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 1.5M (NH4)2SO4 15% Glycerol .1M pH=8.5 Tris Cl/NaOH

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E / Wavelength: 1.54187 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Apr 14, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54187 Å / Relative weight: 1
ReflectionResolution: 2.13→35.51 Å / Num. obs: 7991 / % possible obs: 89.4 % / Redundancy: 2.7 % / Rmerge(I) obs: 0.03 / Net I/σ(I): 20.2
Reflection shellResolution: 2.13→2.15 Å / Rmerge(I) obs: 0.31 / Num. unique obs: 118

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
Aimlessdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.13→35.51 Å / Cor.coef. Fo:Fc: 0.913 / Cor.coef. Fo:Fc free: 0.87 / SU R Cruickshank DPI: 0.505 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.277 / SU Rfree Blow DPI: 0.236 / SU Rfree Cruickshank DPI: 0.225
RfactorNum. reflection% reflectionSelection details
Rfree0.307 397 4.98 %RANDOM
Rwork0.255 ---
obs0.258 7971 88.8 %-
Displacement parametersBiso max: 134.22 Å2 / Biso mean: 53.673 Å2 / Biso min: 33.38 Å2
Baniso -1Baniso -2Baniso -3
1-2.8622 Å20 Å20 Å2
2--2.8622 Å20 Å2
3----5.7245 Å2
Refine analyzeLuzzati coordinate error obs: 0.4 Å
Refinement stepCycle: final / Resolution: 2.13→35.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms749 0 66 58 873
Biso mean--48.89 52.79 -
Num. residues----92
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d381SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes256HARMONIC16
X-RAY DIFFRACTIONt_it1685HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion104SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1880SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1685HARMONIC20.012
X-RAY DIFFRACTIONt_angle_deg3061HARMONIC21.05
X-RAY DIFFRACTIONt_omega_torsion7.41
X-RAY DIFFRACTIONt_other_torsion18.79
LS refinement shellResolution: 2.13→2.19 Å / Rfactor Rfree error: 0 / Total num. of bins used: 19
RfactorNum. reflection% reflection
Rfree0.3361 20 4.76 %
Rwork0.3102 400 -
all0.3115 420 -
obs--54.24 %
Refinement TLS params.Method: refined / Origin x: 19.4751 Å / Origin y: 14.3498 Å / Origin z: 7.7579 Å
111213212223313233
T0.0494 Å2-0.1203 Å2-0.1401 Å2-0.046 Å2-0.0613 Å2---0.127 Å2
L1.1845 °20.3496 °2-0.5703 °2-7.0412 °21.6999 °2--1.3636 °2
S0.1857 Å °-0.3235 Å °-0.206 Å °-0.0785 Å °-0.5562 Å °0.5095 Å °-0.2533 Å °0.1072 Å °0.3704 Å °
Refinement TLS groupSelection details: { A|17 - A|108 }

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