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- PDB-8pwc: Crystal structure of MDM2 with Brigimadlin -

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Basic information

Entry
Database: PDB / ID: 8pwc
TitleCrystal structure of MDM2 with Brigimadlin
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE / Inhibitor / Complex
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 / fibroblast activation / atrial septum development / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / Trafficking of AMPA receptors ...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 / fibroblast activation / atrial septum development / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / Trafficking of AMPA receptors / receptor serine/threonine kinase binding / peroxisome proliferator activated receptor binding / positive regulation of vascular associated smooth muscle cell migration / negative regulation of signal transduction by p53 class mediator / negative regulation of protein processing / SUMO transferase activity / response to steroid hormone / NEDD8 ligase activity / response to iron ion / AKT phosphorylates targets in the cytosol / atrioventricular valve morphogenesis / endocardial cushion morphogenesis / cellular response to peptide hormone stimulus / ventricular septum development / cellular response to alkaloid / positive regulation of muscle cell differentiation / SUMOylation of ubiquitinylation proteins / regulation of postsynaptic neurotransmitter receptor internalization / cardiac septum morphogenesis / blood vessel development / ligase activity / Constitutive Signaling by AKT1 E17K in Cancer / regulation of protein catabolic process / negative regulation of DNA damage response, signal transduction by p53 class mediator / response to magnesium ion / SUMOylation of transcription factors / protein sumoylation / blood vessel remodeling / cellular response to UV-C / cellular response to actinomycin D / cellular response to estrogen stimulus / protein localization to nucleus / ribonucleoprotein complex binding / protein autoubiquitination / positive regulation of vascular associated smooth muscle cell proliferation / NPAS4 regulates expression of target genes / transcription repressor complex / positive regulation of mitotic cell cycle / regulation of heart rate / proteolysis involved in protein catabolic process / Stabilization of p53 / ubiquitin binding / positive regulation of protein export from nucleus / Regulation of RUNX3 expression and activity / Oncogene Induced Senescence / response to cocaine / DNA damage response, signal transduction by p53 class mediator / Regulation of TP53 Activity through Methylation / establishment of protein localization / cellular response to gamma radiation / protein destabilization / RING-type E3 ubiquitin transferase / cellular response to growth factor stimulus / response to toxic substance / centriolar satellite / endocytic vesicle membrane / cellular response to hydrogen peroxide / Signaling by ALK fusions and activated point mutants / protein polyubiquitination / Regulation of TP53 Degradation / ubiquitin-protein transferase activity / disordered domain specific binding / ubiquitin protein ligase activity / p53 binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / negative regulation of neuron projection development / 5S rRNA binding / protein-containing complex assembly / Oxidative Stress Induced Senescence / ubiquitin-dependent protein catabolic process / Regulation of TP53 Activity through Phosphorylation / cellular response to hypoxia / amyloid fibril formation / proteasome-mediated ubiquitin-dependent protein catabolic process / Ub-specific processing proteases / protein ubiquitination / regulation of cell cycle / postsynaptic density / response to xenobiotic stimulus / protein domain specific binding / response to antibiotic / negative regulation of DNA-templated transcription / apoptotic process / positive regulation of cell population proliferation / ubiquitin protein ligase binding / positive regulation of gene expression / negative regulation of apoptotic process / nucleolus / glutamatergic synapse / enzyme binding
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 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
Similarity search - Domain/homology
: / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.461 Å
AuthorsBader, G. / Wolkerstorfer, B.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Mol.Cancer Ther. / Year: 2024
Title: Discovery and Characterization of Brigimadlin, a Novel and Highly Potent MDM2-p53 Antagonist Suitable for Intermittent Dose Schedules.
Authors: Gollner, A. / Rudolph, D. / Weyer-Czernilofsky, U. / Baumgartinger, R. / Jung, P. / Weinstabl, H. / Ramharter, J. / Grempler, R. / Quant, J. / Rinnenthal, J. / Perez Pitarch, A. / Golubovic, ...Authors: Gollner, A. / Rudolph, D. / Weyer-Czernilofsky, U. / Baumgartinger, R. / Jung, P. / Weinstabl, H. / Ramharter, J. / Grempler, R. / Quant, J. / Rinnenthal, J. / Perez Pitarch, A. / Golubovic, B. / Gerlach, D. / Bader, G. / Wetzel, K. / Otto, S. / Mandl, C. / Boehmelt, G. / McConnell, D.B. / Kraut, N. / Sini, P.
History
DepositionJul 20, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 2, 2024Provider: repository / Type: Initial release
Revision 1.1Dec 11, 2024Group: Database references / Structure summary / Category: citation / pdbx_entry_details
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)39,5526
Polymers37,7773
Non-polymers1,7743
Water3,873215
1
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,1842
Polymers12,5921
Non-polymers5911
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,1842
Polymers12,5921
Non-polymers5911
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,1842
Polymers12,5921
Non-polymers5911
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)83.207, 83.207, 42.056
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number145
Space group name H-MP32

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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: 12592.401 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Production host: Escherichia coli (E. coli)
References: UniProt: Q00987, RING-type E3 ubiquitin transferase
#2: Chemical ChemComp-G7I / Brigimadlin


Mass: 591.460 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C31H25Cl2FN4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 215 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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

CrystalDensity Matthews: 2.22 Å3/Da / Density % sol: 44.72 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 22% PEG 3350, 0.1M sodium sulphate, 10 mM manganes chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 2, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.461→41.6 Å / Num. obs: 45565 / % possible obs: 80.8 % / Redundancy: 9.4 % / CC1/2: 0.997 / Rpim(I) all: 0.029 / Net I/σ(I): 11.9
Reflection shellResolution: 1.461→1.553 Å / Num. unique obs: 2282 / CC1/2: 0.51

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Processing

Software
NameVersionClassification
autoPROCdata reduction
XDS(VERSION Feb 5data reduction
autoPROCdata reduction
autoPROC(Version 1.1.7)data scaling
Aimlessdata scaling
BUSTER2.11.8 (8-JUN-2022)refinement
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.461→41.6 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.943 / SU R Cruickshank DPI: 0.1 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.085 / SU Rfree Blow DPI: 0.084 / SU Rfree Cruickshank DPI: 0.085
Details: HYDROGENS WERE FULLY REFINED WITH FULL OCCUPANCY AT NUCLEAR POSITION.
RfactorNum. reflection% reflectionSelection details
Rfree0.2261 2233 4.9 %RANDOM
Rwork0.1994 ---
obs0.2007 45565 80.7 %-
Displacement parametersBiso mean: 41.12 Å2
Baniso -1Baniso -2Baniso -3
1-0.4161 Å20 Å20 Å2
2--0.4161 Å20 Å2
3----0.8321 Å2
Refine analyzeLuzzati coordinate error obs: 0.2 Å
Refinement stepCycle: LAST / Resolution: 1.461→41.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2260 0 123 215 2598
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014910HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.048926HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1452SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes777HARMONIC5
X-RAY DIFFRACTIONt_it4901HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.81
X-RAY DIFFRACTIONt_other_torsion17.89
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion306SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies2HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4772SEMIHARMONIC4
LS refinement shellResolution: 1.461→1.52 Å
RfactorNum. reflection% reflection
Rfree0.2749 -4.71 %
Rwork0.2772 869 -
obs--14.27 %
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)
10.73880.21940.24480.89420.49581.7206-0.0158-0.0208-0.04870.0587-0.08450.05560.093-0.17090.1004-0.027-0.02420.01810.0145-0.0149-0.020230.2164-29.22326.6641
21.32250.30910.74790.6619-0.34032.4226-0.02070.0844-0.01450.0682-0.1289-0.1226-0.12440.160.1496-0.0211-0.0351-0.0151-0.00410.0264-0.018111.5393-42.518821.8253
31.7421-0.08590.3815.28260.48263.17720.2780.42770.5601-0.0890.22210.1344-0.37120.0636-0.5001-0.21720.00920.1873-0.21230.22730.364238.3593-59.722630.4624
40.43440.1678-0.2990.0489-0.30730-0.05630.0334-0.2043-0.0276-0.0358-0.114-0.0007-0.08520.09210.0407-0.0475-0.0001-0.02240.00310.053727.5456-45.319922.801
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }
3X-RAY DIFFRACTION3{ C|* }
4X-RAY DIFFRACTION4{ X|* }

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