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- PDB-3iux: Crystal structure of human MDM2 in complex with a potent miniatur... -

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Basic information

Entry
Database: PDB / ID: 3iux
TitleCrystal structure of human MDM2 in complex with a potent miniature protein inhibitor (18-residues)
Components
  • E3 ubiquitin-protein ligase Mdm2
  • miniature protein inhibitor
KeywordsLIGASE / MDM2 / p53 binding domain / peptide activator of p53 / Host-virus interaction / Metal-binding / Nucleus / Phosphoprotein / Proto-oncogene / Ubl conjugation pathway / Zinc-finger
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 / 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 / response to ether / traversing start control point of mitotic cell cycle / 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 / 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 / cellular response to peptide hormone stimulus / atrioventricular valve morphogenesis / ventricular septum development / endocardial cushion morphogenesis / cellular response to alkaloid / positive regulation of muscle cell differentiation / SUMOylation of ubiquitinylation proteins / 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 / response to magnesium ion / protein sumoylation / ligase activity / SUMOylation of transcription factors / protein localization to nucleus / cellular response to actinomycin D / cellular response to UV-C / blood vessel remodeling / cellular response to estrogen stimulus / protein autoubiquitination / ribonucleoprotein complex binding / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / positive regulation of vascular associated smooth muscle cell proliferation / transcription repressor complex / NPAS4 regulates expression of target genes / regulation of heart rate / proteolysis involved in protein catabolic process / positive regulation of mitotic cell cycle / positive regulation of protein export from nucleus / response to cocaine / ubiquitin binding / Stabilization of p53 / Regulation of RUNX3 expression and activity / protein destabilization / RING-type E3 ubiquitin transferase / cellular response to gamma radiation / establishment of protein localization / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / response to toxic substance / cellular response to hydrogen peroxide / cellular response to growth factor stimulus / protein polyubiquitination / ubiquitin-protein transferase activity / endocytic vesicle membrane / ubiquitin protein ligase activity / disordered domain specific binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Regulation of TP53 Degradation / p53 binding / negative regulation of neuron projection development / 5S rRNA binding / ubiquitin-dependent protein catabolic process / cellular response to hypoxia / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of gene expression / protein-containing complex assembly / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / protein ubiquitination / regulation of cell cycle / 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 / negative regulation of transcription by RNA polymerase II / enzyme binding / protein-containing complex / zinc ion binding / nucleoplasm / identical protein binding
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
ACETATE ION / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.65 Å
AuthorsPazgier, M. / Lu, W.
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2009
Title: Apamin as a template for structure-based rational design of potent peptide activators of p53.
Authors: Li, C. / Pazgier, M. / Liu, M. / Lu, W.Y. / Lu, W.
History
DepositionAug 31, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 27, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Sep 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 / 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

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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: miniature protein inhibitor
C: E3 ubiquitin-protein ligase Mdm2
D: miniature protein inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,80710
Polymers24,5234
Non-polymers2836
Water3,801211
1
A: E3 ubiquitin-protein ligase Mdm2
B: miniature protein inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,4746
Polymers12,2622
Non-polymers2134
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1930 Å2
ΔGint-22 kcal/mol
Surface area6380 Å2
MethodPISA
2
C: E3 ubiquitin-protein ligase Mdm2
D: miniature protein inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,3324
Polymers12,2622
Non-polymers712
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1510 Å2
ΔGint-24 kcal/mol
Surface area6260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.156, 71.569, 75.599
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11B
21D

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Components

#1: 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, p53 binding domain, SWIB domain
Source method: obtained synthetically / Details: MDM2 sequence occurs naturally in humans
References: UniProt: Q00987, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Protein/peptide miniature protein inhibitor


Mass: 2216.630 Da / Num. of mol.: 2 / Source method: obtained synthetically / Details: Desigend miniature protein
#3: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H3O2
#4: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 211 / 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: 2.44 Å3/Da / Density % sol: 49.5 %
Crystal growTemperature: 273 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 2% PEG 400, 0.1 M HEPES, 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: Jul 9, 2001
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.65→50 Å / Num. all: 29543 / Num. obs: 29487 / % possible obs: 99.8 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 5.8 % / Rmerge(I) obs: 0.105 / Net I/σ(I): 15.9
Reflection shellResolution: 1.65→1.68 Å / Redundancy: 5.6 % / Rmerge(I) obs: 0.492 / Mean I/σ(I) obs: 4.2 / Num. unique all: 1452 / Rsym value: 0.492 / % possible all: 4.9

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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: 1.65→20 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.963 / SU B: 3.515 / SU ML: 0.055 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.097 / ESU R Free: 0.091 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.20553 1493 5.1 %RANDOM
Rwork0.18543 ---
obs0.18649 27970 99.85 %-
all-29537 --
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: 20.539 Å2
Baniso -1Baniso -2Baniso -3
1-0.13 Å20 Å20 Å2
2--0.31 Å20 Å2
3----0.44 Å2
Refinement stepCycle: LAST / Resolution: 1.65→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1678 0 15 211 1904
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0221783
X-RAY DIFFRACTIONr_angle_refined_deg1.7032.0062408
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5525206
X-RAY DIFFRACTIONr_dihedral_angle_2_deg43.43623.24374
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.00815335
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.5021510
X-RAY DIFFRACTIONr_chiral_restr0.1230.2263
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211314
X-RAY DIFFRACTIONr_mcbond_it0.9831.51050
X-RAY DIFFRACTIONr_mcangle_it1.64321703
X-RAY DIFFRACTIONr_scbond_it2.9383733
X-RAY DIFFRACTIONr_scangle_it4.8184.5704
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Ens-ID: 1 / Number: 98 / Refine-ID: X-RAY DIFFRACTION

TypeRms dev position (Å)Weight position
loose positional0.35
loose thermal0.9310
LS refinement shellResolution: 1.65→1.693 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.269 91 -
Rwork0.247 2016 -
obs-1452 99.15 %
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)
11.00740.6182-0.08971.1265-0.02730.36910.0223-0.0494-0.06480.0197-0.0358-0.0235-0.00240.00610.01350.01050.00520.00160.0219-0.00430.01114.53914.09727.4726
22.7409-1.7450.4286.3425-0.19121.5307-0.0306-0.1070.2688-0.07960.00290.0561-0.0554-0.08270.02770.03010.00980.00130.0255-0.01460.03972.075829.03377.2953
31.0492-0.21080.33931.62970.06650.59260.0477-0.04370.0467-0.0035-0.06330.0769-0.01770.0390.01560.0058-0.01010.00530.028-0.0180.01537.086221.885730.4987
42.93181.0578-0.31886.5827-0.69992.46610.03150.0149-0.12480.0413-0.070.05610.0696-0.08610.03840.0178-0.0083-0.00510.00690.00110.01914.66426.764130.398
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A27 - 109
2X-RAY DIFFRACTION1A1 - 110
3X-RAY DIFFRACTION1A5 - 209
4X-RAY DIFFRACTION2B1 - 18
5X-RAY DIFFRACTION2B19 - 212
6X-RAY DIFFRACTION3C28 - 109
7X-RAY DIFFRACTION3C1 - 110
8X-RAY DIFFRACTION3C2 - 211
9X-RAY DIFFRACTION4D1 - 18
10X-RAY DIFFRACTION4D19 - 205

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