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- PDB-7kjm: CRYSTAL STRUCTURE OF HUMAN MDM2 IN COMPLEX WITH D-PEPTIDE INHIBIT... -

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Basic information

Entry
Database: PDB / ID: 7kjm
TitleCRYSTAL STRUCTURE OF HUMAN MDM2 IN COMPLEX WITH D-PEPTIDE INHIBITOR (DPMI-OMEGA)
Components
  • D-PMI-omega
  • E3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE/LIGASE INHIBITOR / MDM2 / P53 BINDING DOMAIN / D-PEPTIDE ACTIVATOR OF MDM2 / MDM2-D-PEPTIDE COMPLEX / 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 / 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
: / ISOPROPYL ALCOHOL / DI(HYDROXYETHYL)ETHER / polypeptide(D) / polypeptide(D) (> 10) / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsTolbert, W.D. / Pazgier, M.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI116274 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)P01AI120756 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI129769 United States
CitationJournal: To Be Published
Title: CRYSTAL STRUCTURE OF HUMAN MDM2 IN COMPLEX WITH D-PEPTIDE INHIBITOR (DPMI-OMEGA)
Authors: Tolbert, W.D. / Pazgier, M.
History
DepositionOct 26, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 17, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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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: D-PMI-omega
C: E3 ubiquitin-protein ligase Mdm2
D: D-PMI-omega
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,7168
Polymers23,4784
Non-polymers2374
Water3,099172
1
A: E3 ubiquitin-protein ligase Mdm2
B: D-PMI-omega
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,9766
Polymers11,7392
Non-polymers2374
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1660 Å2
ΔGint-24 kcal/mol
Surface area5900 Å2
MethodPISA
2
C: E3 ubiquitin-protein ligase Mdm2
D: D-PMI-omega


Theoretical massNumber of molelcules
Total (without water)11,7392
Polymers11,7392
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1270 Å2
ΔGint-8 kcal/mol
Surface area6000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)37.355, 38.451, 138.022
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP22121

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Components

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Protein / Polypeptide(D) , 2 types, 4 molecules ACBD

#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: 10044.889 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: Q00987, RING-type E3 ubiquitin transferase
#2: Polypeptide(D) D-PMI-omega


Type: Peptide-like / Class: Inhibitor / Mass: 1694.346 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) / References: BIRD: PRD_002455

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Non-polymers , 4 types, 176 molecules

#3: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#4: Chemical ChemComp-IPA / ISOPROPYL ALCOHOL / 2-PROPANOL


Mass: 60.095 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O / Comment: alkaloid*YM
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 172 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.11 Å3/Da / Density % sol: 41.73 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 30% isopropanol, 15% PEG 8000, 0.1 M imidazole pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 29, 2019
RadiationMonochromator: Si (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.4→50 Å / Num. obs: 40059 / % possible obs: 99.2 % / Redundancy: 4.4 % / CC1/2: 0.988 / Rmerge(I) obs: 0.09 / Rpim(I) all: 0.048 / Net I/σ(I): 31.4
Reflection shellResolution: 1.4→1.42 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.867 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 1990 / CC1/2: 0.765 / Rpim(I) all: 0.471 / % possible all: 99.5

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Processing

Software
NameVersionClassification
PHENIX(1.17.1_3660: ???)refinement
REFMAC5.8.0258refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3lnj

3lnj


Resolution: 1.4→36.06 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 22.7 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2099 1978 4.94 %
Rwork0.1843 --
obs0.1856 40012 99.1 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.4→36.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1643 0 13 172 1828
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0131729
X-RAY DIFFRACTIONf_angle_d1.582328
X-RAY DIFFRACTIONf_dihedral_angle_d17.136291
X-RAY DIFFRACTIONf_chiral_restr0.092256
X-RAY DIFFRACTIONf_plane_restr0.009283
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4-1.430.33571340.29212657X-RAY DIFFRACTION98
1.43-1.470.33271340.27562664X-RAY DIFFRACTION99
1.47-1.510.28491570.24052662X-RAY DIFFRACTION100
1.52-1.560.2681470.22632678X-RAY DIFFRACTION99
1.56-1.620.23861450.21992704X-RAY DIFFRACTION99
1.62-1.680.25021460.19852705X-RAY DIFFRACTION100
1.68-1.760.21391550.18912656X-RAY DIFFRACTION99
1.76-1.850.24491440.19122704X-RAY DIFFRACTION99
1.85-1.970.23371300.19772717X-RAY DIFFRACTION100
1.97-2.120.25121450.19022730X-RAY DIFFRACTION100
2.12-2.340.19221380.17812739X-RAY DIFFRACTION99
2.34-2.670.24621360.192740X-RAY DIFFRACTION99
2.67-3.370.21131270.18982799X-RAY DIFFRACTION99
3.37-36.060.16621400.16222879X-RAY DIFFRACTION97
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)
11.65660.16550.73082.8937-0.04034.40820.0154-0.0561-0.09120.00430.039-0.0895-0.0970.1102-0.05580.08940.02070.00690.1299-0.00170.1575-8.4815-14.846128.2391
22.18951.26930.48611.8264-0.42951.90420.0010.04280.2378-0.0639-0.04320.2506-0.32370.01120.13770.20120.0373-0.02430.18210.00810.2347-14.6061-4.935923.8602
31.9473-0.6511-0.66833.31491.31233.36220.06690.1777-0.101-0.1868-0.19590.25140.0741-0.33380.10580.21580.00180.00060.2077-0.01160.1931-24.2589-24.273212.0179
44.45521.4355-0.66480.74860.62583.01680.14080.62240.3971-0.4901-0.14160.2159-0.6602-0.5138-0.03010.43380.09750.00170.30860.03030.2488-23.1756-12.17798.2175
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain 'A' and resid 25 through 109)
2X-RAY DIFFRACTION2(chain 'B' and resid 1 through 12)
3X-RAY DIFFRACTION3(chain 'C' and resid 26 through 109)
4X-RAY DIFFRACTION4(chain 'D' and resid 1 through 12)

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