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- PDB-4zfi: Structure of Mdm2 with low molecular weight inhibitor -

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Basic information

Entry
Database: PDB / ID: 4zfi
TitleStructure of Mdm2 with low molecular weight inhibitor
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE / p53-binding protein Mdm2 / Oncoprotein Mdm2 / Double minute 2 protein / Hdm2 / small molecule inhibitor
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 / response to iron ion / negative regulation of protein processing / SUMO transferase activity / 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 / negative regulation of DNA damage response, signal transduction by p53 class mediator / ligase activity / response to magnesium ion / protein sumoylation / SUMOylation of transcription factors / 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 / proteolysis involved in protein catabolic process / positive regulation of protein export from nucleus / response to cocaine / ubiquitin binding / Stabilization of p53 / Regulation of RUNX3 expression and activity / Signaling by ALK fusions and activated point mutants / protein destabilization / RING-type E3 ubiquitin transferase / establishment of protein localization / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / cellular response to gamma radiation / response to toxic substance / 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 / Regulation of TP53 Degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / p53 binding / negative regulation of neuron projection development / 5S rRNA binding / cellular response to hypoxia / ubiquitin-dependent protein catabolic process / 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 / regulation of cell cycle / protein ubiquitination / 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 / 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
Chem-4NJ / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2 Å
AuthorsZak, K.M. / Twarda-Clapa, A. / Wrona, E.M. / Grudnik, P. / Dubin, G. / Holak, T.A.
Funding support Poland, 2items
OrganizationGrant numberCountry
the Foundation for Polish ScienceTEAM Programme Poland
the polish National Centre of ScienceUMO-2011/01/D/NZ1/01169 Poland
CitationJournal: ACS Chem. Biol. / Year: 2016
Title: A Unique Mdm2-Binding Mode of the 3-Pyrrolin-2-one- and 2-Furanone-Based Antagonists of the p53-Mdm2 Interaction.
Authors: Surmiak, E. / Twarda-Clapa, A. / Zak, K.M. / Musielak, B. / Tomala, M.D. / Kubica, K. / Grudnik, P. / Madej, M. / Jablonski, M. / Potempa, J. / Kalinowska-Tluscik, J. / Domling, A. / Dubin, G. / Holak, T.A.
History
DepositionApr 21, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Oct 19, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 28, 2016Group: Database references
Revision 1.2Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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: E3 ubiquitin-protein ligase Mdm2
D: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,6458
Polymers45,5984
Non-polymers2,0474
Water5,639313
1
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,9112
Polymers11,3991
Non-polymers5121
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,9112
Polymers11,3991
Non-polymers5121
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,9112
Polymers11,3991
Non-polymers5121
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,9112
Polymers11,3991
Non-polymers5121
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.360, 70.250, 96.440
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: 0 / Refine code: 0

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11GLNGLNASNASNAA18 - 1112 - 95
21GLNGLNASNASNBB18 - 1112 - 95
12GLNGLNVALVALAA18 - 1092 - 93
22GLNGLNVALVALCC18 - 1092 - 93
13ILEILEVALVALAA19 - 1103 - 94
23ILEILEVALVALDD19 - 1103 - 94
14GLNGLNVALVALBB18 - 1092 - 93
24GLNGLNVALVALCC18 - 1092 - 93
15ILEILEVALVALBB19 - 1103 - 94
25ILEILEVALVALDD19 - 1103 - 94
16ILEILEVALVALCC19 - 1093 - 93
26ILEILEVALVALDD19 - 1093 - 93

NCS ensembles :
ID
1
2
3
4
5
6

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Components

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


Mass: 11399.375 Da / Num. of mol.: 4 / Fragment: UNP RESIDUES 18-113
Source method: isolated from a genetically manipulated source
Details: p53 binding domain of Mdm2 / Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Plasmid: pET-20 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q00987, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Chemical
ChemComp-4NJ / (5S)-3,5-bis(4-chlorobenzyl)-4-(6-chloro-1H-indol-3-yl)-5-hydroxy-1-methyl-1,5-dihydro-2H-pyrrol-2-one


Mass: 511.827 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H21Cl3N2O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 313 / 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: 2.46 Å3/Da / Density % sol: 50.1 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.1 M HEPES pH 7.5, 0.2 M sodium chloride, 25% (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.541 Å
DetectorType: MAR CCD 130 mm / Detector: CCD / Date: Jun 5, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.541 Å / Relative weight: 1
ReflectionResolution: 2→56.78 Å / Num. all: 180767 / Num. obs: 31037 / % possible obs: 99.72 % / Redundancy: 5.8 % / Rmerge(I) obs: 0.108 / Net I/σ(I): 8.38
Reflection shellResolution: 2→2.071 Å / Redundancy: 5.7 % / Rmerge(I) obs: 0.424 / Mean I/σ(I) obs: 2.61 / % possible all: 99.54

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.24 Å24.12 Å
Translation3.24 Å24.12 Å

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
SCALAdata scaling
PHASER2.5.5phasing
REFMAC5.8.0049refinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3LBL

3lbl


Resolution: 2→56.78 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.932 / WRfactor Rfree: 0.2377 / WRfactor Rwork: 0.1963 / FOM work R set: 0.7897 / SU B: 8.235 / SU ML: 0.127 / SU R Cruickshank DPI: 0.1874 / SU Rfree: 0.1688 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.187 / ESU R Free: 0.169 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2433 1564 5 %RANDOM
Rwork0.1977 ---
obs0.1999 29436 99.53 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 71.78 Å2 / Biso mean: 30.395 Å2 / Biso min: 15.27 Å2
Baniso -1Baniso -2Baniso -3
1--0.91 Å20 Å2-0 Å2
2--3.58 Å2-0 Å2
3----2.67 Å2
Refinement stepCycle: final / Resolution: 2→56.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2961 0 136 313 3410
Biso mean--24.67 38.37 -
Num. residues----378
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0193178
X-RAY DIFFRACTIONr_bond_other_d0.0090.023012
X-RAY DIFFRACTIONr_angle_refined_deg2.1592.044332
X-RAY DIFFRACTIONr_angle_other_deg1.53536883
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3665376
X-RAY DIFFRACTIONr_dihedral_angle_2_deg43.32523.739115
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.21715530
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.7751512
X-RAY DIFFRACTIONr_chiral_restr0.1010.2489
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.0213467
X-RAY DIFFRACTIONr_gen_planes_other0.0080.02717
X-RAY DIFFRACTIONr_mcbond_it2.252.4961506
X-RAY DIFFRACTIONr_mcbond_other2.2292.4941505
X-RAY DIFFRACTIONr_mcangle_it3.1083.7211875
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A55910.06
12B55910.06
21A51720.14
22C51720.14
31A49340.13
32D49340.13
41B50410.14
42C50410.14
51B49040.13
52D49040.13
61C50040.11
62D50040.11
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.276 103 -
Rwork0.255 2152 -
all-2255 -
obs--99.51 %
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)
10.3917-0.0958-0.20270.40280.0910.72840.0430.0070.0244-0.02-0.0247-0.0392-0.0114-0.0674-0.01830.02080.01360.00560.02160.00780.00899.76320.471121.8971
20.530.072-0.39010.40810.02581.29820.0404-0.00690.0350.02510.0090.0430.01650.063-0.04940.0126-0.00260.00550.0176-0.0120.0154-9.34940.20625.2326
30.37560.0809-0.04610.35030.24440.96850.01840.0291-0.02010.00430.0074-0.0115-0.0352-0.0323-0.02580.01870.00480.01250.0080.00860.0251-17.49034.44230.8574
40.473-0.0030.1830.591-0.18251.1753-0.0089-0.0077-0.02060.01730.02010.0186-0.02740.0464-0.01130.0099-0.00320.01240.0047-0.00270.016217.47774.5399-3.9116
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A18 - 112
2X-RAY DIFFRACTION2B17 - 113
3X-RAY DIFFRACTION3C18 - 110
4X-RAY DIFFRACTION4D19 - 111

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