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- PDB-4jwr: Co-crystal structure of MDM2 with inhibitor {(2S,5R,6S)-6-(3-chlo... -

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Basic information

Entry
Database: PDB / ID: 4jwr
TitleCo-crystal structure of MDM2 with inhibitor {(2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-[(2S)-1-hydroxybutan-2-yl]-3-oxomorpholin-2-yl}acetic acid
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE/LIGASE INHIBITOR / p53 / protein-protein interaction / LIGASE-LIGASE 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 / 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 / response to steroid hormone / SUMO transferase activity / 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 / protein autoubiquitination / blood vessel remodeling / cellular response to estrogen stimulus / 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 / response to cocaine / positive regulation of protein export from nucleus / ubiquitin binding / Stabilization of p53 / Regulation of RUNX3 expression and activity / protein destabilization / cellular response to gamma radiation / 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 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
Chem-1MY / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 Å
AuthorsShaffer, P.L.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Rational Design and Binding Mode Duality of MDM2-p53 Inhibitors.
Authors: Gonzalez-Lopez de Turiso, F. / Sun, D. / Rew, Y. / Bartberger, M.D. / Beck, H.P. / Canon, J. / Chen, A. / Chow, D. / Correll, T.L. / Huang, X. / Julian, L.D. / Kayser, F. / Lo, M.C. / Long, ...Authors: Gonzalez-Lopez de Turiso, F. / Sun, D. / Rew, Y. / Bartberger, M.D. / Beck, H.P. / Canon, J. / Chen, A. / Chow, D. / Correll, T.L. / Huang, X. / Julian, L.D. / Kayser, F. / Lo, M.C. / Long, A.M. / McMinn, D. / Oliner, J.D. / Osgood, T. / Powers, J.P. / Saiki, A.Y. / Schneider, S. / Shaffer, P. / Xiao, S.H. / Yakowec, P. / Yan, X. / Ye, Q. / Yu, D. / Zhao, X. / Zhou, J. / Medina, J.C. / Olson, S.H.
History
DepositionMar 27, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2013Provider: repository / Type: Initial release
Revision 1.1Jun 5, 2013Group: Database references
Revision 1.2Sep 20, 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

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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,6546
Polymers33,2973
Non-polymers1,3573
Water1,20767
1
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,5512
Polymers11,0991
Non-polymers4521
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,5512
Polymers11,0991
Non-polymers4521
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,5512
Polymers11,0991
Non-polymers4521
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)56.446, 97.796, 104.194
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11B-301-

HOH

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
31C

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Components

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


Mass: 11099.000 Da / Num. of mol.: 3 / Fragment: UNP residues 17-111
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, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Chemical ChemComp-1MY / {(2S,5R,6S)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-[(2S)-1-hydroxybutan-2-yl]-3-oxomorpholin-2-yl}acetic acid


Mass: 452.328 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C22H23Cl2NO5
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 67 / 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: 2.16 Å3/Da / Density % sol: 43.04 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 100 mM citrate, pH 5.0, 1.9-2.4 M ammonium sulfate, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.9795 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Jan 24, 2012
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.35→50 Å / Num. obs: 12411 / % possible obs: 99.8 % / Redundancy: 5.5 % / Rmerge(I) obs: 0.124 / Χ2: 1.18 / Net I/σ(I): 7.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.35-2.435.20.72712010.966198.7
2.43-2.535.60.47912061.0191100
2.53-2.655.60.45312310.9381100
2.65-2.795.60.32412160.9651100
2.79-2.965.60.24512581.0661100
2.96-3.195.50.17112121.1431100
3.19-3.515.50.13212471.2891100
3.51-4.025.50.08512411.2441100
4.02-5.065.50.08812601.5511100
5.06-505.20.06113391.59199.7

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMAC5.5.0109refinement
PDB_EXTRACT3.11data extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4JV9

4jv9


Resolution: 2.35→48.9 Å / Cor.coef. Fo:Fc: 0.919 / Cor.coef. Fo:Fc free: 0.9 / Occupancy max: 1 / Occupancy min: 0.5 / SU B: 21.268 / SU ML: 0.226 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.544 / ESU R Free: 0.283 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2661 610 5 %RANDOM
Rwork0.235 ---
obs0.2365 12316 99.35 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 55.51 Å2 / Biso mean: 33.7095 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-0.19 Å20 Å20 Å2
2--0.34 Å20 Å2
3----0.53 Å2
Refinement stepCycle: LAST / Resolution: 2.35→48.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2153 0 90 67 2310
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0222291
X-RAY DIFFRACTIONr_angle_refined_deg1.1062.0483098
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3675258
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.88923.10387
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.04815416
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.4831512
X-RAY DIFFRACTIONr_chiral_restr0.0780.2360
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0211641
X-RAY DIFFRACTIONr_mcbond_it0.1331.51314
X-RAY DIFFRACTIONr_mcangle_it0.22922145
X-RAY DIFFRACTIONr_scbond_it0.4773977
X-RAY DIFFRACTIONr_scangle_it0.714.5953
Refine LS restraints NCS

Ens-ID: 1 / Refine-ID: X-RAY DIFFRACTION

Dom-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
1A352TIGHT POSITIONAL0.010.05
2B352TIGHT POSITIONAL0.010.05
3C352TIGHT POSITIONAL0.010.05
1A365MEDIUM POSITIONAL0.010.5
2B365MEDIUM POSITIONAL0.010.5
3C365MEDIUM POSITIONAL0.010.5
1A352TIGHT THERMAL0.030.5
2B352TIGHT THERMAL0.030.5
3C352TIGHT THERMAL0.030.5
1A365MEDIUM THERMAL0.032
2B365MEDIUM THERMAL0.032
3C365MEDIUM THERMAL0.032
LS refinement shellResolution: 2.35→2.409 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.352 41 -
Rwork0.306 841 -
all-882 -
obs--98.88 %
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)
12.5663-0.91550.88133.1188-0.12513.0755-0.1026-0.01720.0618-0.31790.1079-0.00980.1514-0.1277-0.00520.0762-0.01650.00240.0765-0.01630.07671.8322-16.34663.2137
21.94950.12510.52262.56561.08971.51040.20170.03580.1374-0.1291-0.18550.09930.1130.0998-0.01620.11130.01710.0040.09430.00640.08415.7136-8.602819.9385
31.4314-1.50210.66995.4794-2.53873.6471-0.1493-0.3216-0.04290.01510.1639-0.1540.0112-0.2561-0.01460.04290.01130.04030.1273-0.01620.080613.8493-38.296814.1837
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A19 - 110
2X-RAY DIFFRACTION1B201
3X-RAY DIFFRACTION2B19 - 110
4X-RAY DIFFRACTION2C201
5X-RAY DIFFRACTION3C19 - 110
6X-RAY DIFFRACTION3A201

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