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- PDB-4jvr: Co-crystal structure of MDM2 with inhibitor (2'S,3R,4'S,5'R)-N-(2... -

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Basic information

Entry
Database: PDB / ID: 4jvr
TitleCo-crystal structure of MDM2 with inhibitor (2'S,3R,4'S,5'R)-N-(2-aminoethyl)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxamide
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-1MT / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsHuang, X. / Gonzalez-Lopez de Turiso, F. / Sun, D. / Yosup, R. / Bartberger, M.D. / Beck, H.P. / Cannon, J. / Shaffer, P. / Oliner, J.D. / Olson, S.H. / Medina, J.C.
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 26, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2013Provider: repository / Type: Initial release
Revision 1.1Jun 5, 2013Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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
C: E3 ubiquitin-protein ligase Mdm2
E: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9906
Polymers33,4683
Non-polymers1,5223
Water3,999222
1
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,6632
Polymers11,1561
Non-polymers5071
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
C: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,6632
Polymers11,1561
Non-polymers5071
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
E: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,6632
Polymers11,1561
Non-polymers5071
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)56.678, 98.376, 104.574
Angle α, β, γ (deg.)90, 90, 90
Int Tables number20
Space group name H-MC2221

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Components

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


Mass: 11156.052 Da / Num. of mol.: 3 / Fragment: UNP residues 18-111
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-1MT / (2'S,3R,4'S,5'R)-N-(2-aminoethyl)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxamide


Mass: 507.428 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C25H29Cl2FN4O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 222 / 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: 2.18 Å3/Da / Density % sol: 43.52 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 100 mM citrate, pH 5.0, 1.5-2.0 M ammonium sulfate, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD
RadiationMonochromator: Diamond(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 1.6→30 Å / Num. obs: 36784 / % possible obs: 95.4 % / Observed criterion σ(I): -3 / Rmerge(I) obs: 0.034
Reflection shellResolution: 1.6→1.66 Å / Rmerge(I) obs: 0.56 / % possible all: 66.9

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Processing

Software
NameClassification
HKL-2000data collection
AMoREphasing
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→30 Å / Occupancy max: 1 / Occupancy min: 0 / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.27 1609 4.9 %RANDOM
Rwork0.256 30734 --
obs-32343 99.3 %-
Displacement parametersBiso max: 76.18 Å2 / Biso mean: 30.3938 Å2 / Biso min: 13.1 Å2
Baniso -1Baniso -2Baniso -3
1-2.289 Å20 Å20 Å2
2--2.198 Å20 Å2
3----4.487 Å2
Refinement stepCycle: LAST / Resolution: 1.7→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2134 0 102 222 2458
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_mcbond_it1.1691.5
X-RAY DIFFRACTIONc_scbond_it1.8022
X-RAY DIFFRACTIONc_mcangle_it1.9562
X-RAY DIFFRACTIONc_scangle_it2.7332.5
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1mdm2.param
X-RAY DIFFRACTION22098457.xprm
X-RAY DIFFRACTION3MSI_CNX_TOPPAR:water_rep.param

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