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- PDB-3lnz: Crystal structure of human MDM2 with a 12-mer peptide inhibitor P... -

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Basic information

Entry
Database: PDB / ID: 3lnz
TitleCrystal structure of human MDM2 with a 12-mer peptide inhibitor PMI (N8A mutant)
Components
  • 12-mer peptide inhibitor
  • E3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE/LIGASE INHIBITOR / P53-BINDING PROTEIN of MDM2 / ONCOPROTEIN MDM2 / HUMAN DOUBLE MINUTE 2 PROTEIN / HDM2 / MDM2-peptide inhibitor complex / p53 peptide activator N8A-PMI / Host-virus interaction / Ligase / Metal-binding / Nucleus / Phosphoprotein / Proto-oncogene / Ubl conjugation pathway / Zinc-finger / LIGASE-LIGASE 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 / response to ether / 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 / traversing start control point of mitotic cell cycle / response to ether / 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 / SUMO transferase activity / negative regulation of protein processing / response to iron ion / response to steroid hormone / NEDD8 ligase activity / cellular response to peptide hormone stimulus / AKT phosphorylates targets in the cytosol / atrioventricular valve morphogenesis / ventricular septum development / endocardial cushion morphogenesis / positive regulation of muscle cell differentiation / cellular response to alkaloid / SUMOylation of ubiquitinylation proteins / regulation of protein catabolic process / blood vessel development / cardiac septum morphogenesis / ligase activity / Constitutive Signaling by AKT1 E17K in Cancer / response to magnesium ion / negative regulation of DNA damage response, signal transduction by p53 class mediator / 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 / transcription repressor complex / NPAS4 regulates expression of target genes / regulation of heart rate / positive regulation of mitotic cell cycle / positive regulation of protein export from nucleus / ubiquitin binding / proteolysis involved in protein catabolic process / response to cocaine / Stabilization of p53 / protein destabilization / Regulation of RUNX3 expression and activity / establishment of protein localization / RING-type E3 ubiquitin transferase / cellular response to growth factor stimulus / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / cellular response to gamma radiation / response to toxic substance / cellular response to hydrogen peroxide / protein polyubiquitination / ubiquitin-protein transferase activity / disordered domain specific binding / endocytic vesicle membrane / ubiquitin protein ligase activity / p53 binding / Signaling by ALK fusions and activated point mutants / Regulation of TP53 Degradation / negative regulation of neuron projection development / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / 5S rRNA binding / cellular response to hypoxia / ubiquitin-dependent protein catabolic process / regulation of gene expression / protein-containing complex assembly / Oxidative Stress Induced Senescence / proteasome-mediated ubiquitin-dependent protein catabolic process / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / regulation of cell cycle / Ub-specific processing proteases / protein ubiquitination / response to xenobiotic stimulus / protein domain specific binding / response to antibiotic / negative regulation of DNA-templated transcription / ubiquitin protein ligase binding / positive regulation of cell population proliferation / positive regulation of gene expression / negative regulation of apoptotic process / nucleolus / apoptotic process / negative regulation of transcription by RNA polymerase II / enzyme binding / 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
E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsPazgier, M. / Lu, W.
CitationJournal: J.Mol.Biol. / Year: 2010
Title: Systematic mutational analysis of peptide inhibition of the p53-MDM2/MDMX interactions.
Authors: Li, C. / Pazgier, M. / Li, C. / Yuan, W. / Liu, M. / Wei, G. / Lu, W.Y. / Lu, W.
History
DepositionFeb 3, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 9, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / 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_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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

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Assembly

Deposited unit
A: E3 ubiquitin-protein ligase Mdm2
B: 12-mer peptide inhibitor
C: E3 ubiquitin-protein ligase Mdm2
D: 12-mer peptide inhibitor
E: E3 ubiquitin-protein ligase Mdm2
F: 12-mer peptide inhibitor
G: E3 ubiquitin-protein ligase Mdm2
H: 12-mer peptide inhibitor
I: E3 ubiquitin-protein ligase Mdm2
J: 12-mer peptide inhibitor
K: E3 ubiquitin-protein ligase Mdm2
L: 12-mer peptide inhibitor
M: E3 ubiquitin-protein ligase Mdm2
N: 12-mer peptide inhibitor
O: E3 ubiquitin-protein ligase Mdm2
P: 12-mer peptide inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)91,71924
Polymers91,43516
Non-polymers2848
Water12,647702
1
A: E3 ubiquitin-protein ligase Mdm2
B: 12-mer peptide inhibitor
hetero molecules

A: E3 ubiquitin-protein ligase Mdm2
B: 12-mer peptide inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,9306
Polymers22,8594
Non-polymers712
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555-y,-x,-z+1/31
Buried area4340 Å2
ΔGint-51 kcal/mol
Surface area9570 Å2
MethodPISA
2
C: E3 ubiquitin-protein ligase Mdm2
D: 12-mer peptide inhibitor
hetero molecules

C: E3 ubiquitin-protein ligase Mdm2
D: 12-mer peptide inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,9306
Polymers22,8594
Non-polymers712
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_555x,x-y,-z1
Buried area4190 Å2
ΔGint-55 kcal/mol
Surface area9520 Å2
MethodPISA
3
E: E3 ubiquitin-protein ligase Mdm2
F: 12-mer peptide inhibitor
G: E3 ubiquitin-protein ligase Mdm2
H: 12-mer peptide inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,9306
Polymers22,8594
Non-polymers712
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4350 Å2
ΔGint-56 kcal/mol
Surface area9430 Å2
MethodPISA
4
I: E3 ubiquitin-protein ligase Mdm2
J: 12-mer peptide inhibitor
hetero molecules

K: E3 ubiquitin-protein ligase Mdm2
L: 12-mer peptide inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,9306
Polymers22,8594
Non-polymers712
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555-y,-x,-z+1/31
Buried area4360 Å2
ΔGint-56 kcal/mol
Surface area9420 Å2
MethodPISA
5
M: E3 ubiquitin-protein ligase Mdm2
N: 12-mer peptide inhibitor
hetero molecules

M: E3 ubiquitin-protein ligase Mdm2
N: 12-mer peptide inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,0018
Polymers22,8594
Non-polymers1424
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_545x,x-y-1,-z1
Buried area4530 Å2
ΔGint-70 kcal/mol
Surface area9220 Å2
MethodPISA
6
O: E3 ubiquitin-protein ligase Mdm2
P: 12-mer peptide inhibitor

O: E3 ubiquitin-protein ligase Mdm2
P: 12-mer peptide inhibitor


Theoretical massNumber of molelcules
Total (without water)22,8594
Polymers22,8594
Non-polymers00
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_665-y+1,-x+1,-z+1/31
Buried area3870 Å2
ΔGint-32 kcal/mol
Surface area9760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.544, 90.544, 196.837
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number153
Space group name H-MP3212

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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.: 8 / Fragment: UNP residues 25-109, P53 BINDING DOMAIN / Source method: obtained synthetically / Details: This sequence occurs naturally in humans.
References: UniProt: Q00987, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Protein/peptide
12-mer peptide inhibitor


Mass: 1384.532 Da / Num. of mol.: 8 / Mutation: N8A / Source method: obtained synthetically / Details: Synthetic peptide found by phage dissplay
#3: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 702 / 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: 2.55 Å3/Da / Density % sol: 51.78 %
Crystal growTemperature: 273 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.2 M Mg acetate tetrahydrate sulfate, 0.1 M cacodylate trihydrate, 20% PEG 8000, pH 6.5, 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: Jan 6, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.949→78.413 Å / Num. all: 67750 / Num. obs: 67730 / % possible obs: 99 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 8.2 % / Rmerge(I) obs: 0.119 / Rsym value: 0.152 / Net I/σ(I): 23.1
Reflection shellResolution: 1.95→1.98 Å / Redundancy: 8.1 % / Rmerge(I) obs: 0.575 / Mean I/σ(I) obs: 4 / Rsym value: 0.556 / % possible all: 100

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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: 1.95→20 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.916 / SU B: 7.873 / SU ML: 0.126 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.191 / ESU R Free: 0.175 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.26687 3425 5.1 %RANDOM
Rwork0.21952 ---
obs0.22186 64239 99.99 %-
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: 27.757 Å2
Baniso -1Baniso -2Baniso -3
1-0.79 Å20.39 Å20 Å2
2--0.79 Å20 Å2
3----1.18 Å2
Refinement stepCycle: LAST / Resolution: 1.95→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6266 0 8 702 6976
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0226436
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.8461.9888682
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8545745
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.68922.996267
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.069151224
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.2961533
X-RAY DIFFRACTIONr_chiral_restr0.1310.2983
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0214629
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.9971.53771
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.58226120
X-RAY DIFFRACTIONr_scbond_it2.76832665
X-RAY DIFFRACTIONr_scangle_it3.8724.52561
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.949→1.999 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.318 223 -
Rwork0.226 4717 -
obs--100 %
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)
12.40330.766-0.10841.65020.2191.48590.07650.0523-0.00060.0158-0.0980.0204-0.02270.0060.02150.0060.0135-0.00270.0514-0.00960.002237.4148-26.406721.693
23.3528-1.23680.1552.5880.14972.19790.10160.05940.24760.1532-0.18810.0264-0.00850.08150.08650.0574-0.06380.00010.08490.01790.04733.842425.783810.6519
31.3416-0.16920.05262.9487-0.14582.17020.00150.1255-0.0815-0.07590.08970.0187-0.0409-0.0832-0.09120.00370.00120.00280.0236-0.00080.010617.568-22.8725-10.1714
41.0649-0.80330.15791.90240.47851.60690.09540.01820.0252-0.0345-0.14810.0232-0.037-0.04310.05270.0140.00130.00390.0360.00480.008914.7711-13.06411.2909
50.97490.68730.58571.9490.37281.91220.16560.10060.0222-0.0135-0.06910.1359-0.21410.0808-0.09650.11050.04050.03220.05370.02370.058811.299812.505322.3375
63.10471.0467-0.13412.08590.70921.56380.10640.0129-0.2808-0.0323-0.0805-0.02370.1191-0.0599-0.02590.0292-0.0114-0.02790.04560.01940.0449-7.7043-25.651721.6541
72.3889-0.8549-0.09631.77760.46761.74220.066-0.07750.02440.0874-0.15780.1012-0.00370.04850.09180.0121-0.02250.00860.048-0.01420.011460.5629-12.900711.1821
84.00211.64690.72152.67520.35872.91040.07060.0477-0.0923-0.1081-0.0905-0.0428-0.0040.11390.01990.0140.0110.00280.01820.00060.011656.283412.830322.2421
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A25 - 109
2X-RAY DIFFRACTION1A5
3X-RAY DIFFRACTION2C27 - 108
4X-RAY DIFFRACTION2C8
5X-RAY DIFFRACTION3E27 - 108
6X-RAY DIFFRACTION3E2
7X-RAY DIFFRACTION4G26 - 109
8X-RAY DIFFRACTION4G4
9X-RAY DIFFRACTION5I26 - 108
10X-RAY DIFFRACTION5I1
11X-RAY DIFFRACTION6K26 - 108
12X-RAY DIFFRACTION6K7
13X-RAY DIFFRACTION7M27 - 109
14X-RAY DIFFRACTION7M3 - 6
15X-RAY DIFFRACTION8O26 - 108

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