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- PDB-5trf: MDM2 in complex with SAR405838 -

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Basic information

Entry
Database: PDB / ID: 5trf
TitleMDM2 in complex with SAR405838
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE/LIGASE INHIBITOR / P53-BINDING PROTEIN / ONCOPROTEIN / DOUBLE MINUTE 2 PROTEIN / SMALL MOLECULE INHIBITOR / 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 / negative regulation of DNA damage response, signal transduction by p53 class mediator / SUMOylation of transcription factors / response to magnesium ion / 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 / proteolysis involved in protein catabolic process / ubiquitin binding / response to cocaine / Stabilization of p53 / Regulation of RUNX3 expression and activity / protein destabilization / establishment of protein localization / RING-type E3 ubiquitin transferase / Oncogene Induced Senescence / cellular response to gamma radiation / Regulation of TP53 Activity through Methylation / cellular response to growth factor stimulus / cellular response to hydrogen peroxide / response to toxic substance / 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
Chem-7HC / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 Å
AuthorsMeagher, J.L. / Stuckey, J.A.
CitationJournal: Cancer Res. / Year: 2014
Title: SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression.
Authors: Wang, S. / Sun, W. / Zhao, Y. / McEachern, D. / Meaux, I. / Barriere, C. / Stuckey, J.A. / Meagher, J.L. / Bai, L. / Liu, L. / Hoffman-Luca, C.G. / Lu, J. / Shangary, S. / Yu, S. / Bernard, ...Authors: Wang, S. / Sun, W. / Zhao, Y. / McEachern, D. / Meaux, I. / Barriere, C. / Stuckey, J.A. / Meagher, J.L. / Bai, L. / Liu, L. / Hoffman-Luca, C.G. / Lu, J. / Shangary, S. / Yu, S. / Bernard, D. / Aguilar, A. / Dos-Santos, O. / Besret, L. / Guerif, S. / Pannier, P. / Gorge-Bernat, D. / Debussche, L.
History
DepositionOct 26, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 9, 2016Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2017Group: Derived calculations / Refinement description / Category: pdbx_struct_oper_list / software
Item: _pdbx_struct_oper_list.symmetry_operation / _software.classification / _software.name
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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
D: E3 ubiquitin-protein ligase Mdm2
E: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,27720
Polymers62,5325
Non-polymers3,74515
Water4,738263
1
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,4416
Polymers12,5061
Non-polymers9355
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,2534
Polymers12,5061
Non-polymers7473
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,3495
Polymers12,5061
Non-polymers8434
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,0692
Polymers12,5061
Non-polymers5631
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
E: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,1653
Polymers12,5061
Non-polymers6592
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area150 Å2
ΔGint-11 kcal/mol
Surface area5670 Å2
MethodPISA
6
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules

A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,88212
Polymers25,0132
Non-polymers1,87010
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_555-y,-x,-z+1/21
Buried area1940 Å2
ΔGint-32 kcal/mol
Surface area10050 Å2
MethodPISA
7
B: E3 ubiquitin-protein ligase Mdm2
hetero molecules

D: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,3226
Polymers25,0132
Non-polymers1,3094
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_455y-1/2,-x+1/2,z+1/41
Buried area2170 Å2
ΔGint-10 kcal/mol
Surface area9700 Å2
MethodPISA
8
C: E3 ubiquitin-protein ligase Mdm2
hetero molecules

C: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,69810
Polymers25,0132
Non-polymers1,6868
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_556y,x,-z+11
Buried area2730 Å2
ΔGint-31 kcal/mol
Surface area10120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)138.849, 138.849, 83.707
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212

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Components

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


Mass: 12506.351 Da / Num. of mol.: 5 / Fragment: residues 10-118
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-7HC / (2'S,3R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-N-(trans-4-hydroxycyclohexyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxamide


Mass: 562.503 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Formula: C29H34Cl2FN3O3
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: SO4
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 7
Source method: isolated from a genetically manipulated source
Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 263 / 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: 3.47 Å3/Da / Density % sol: 64.52 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 2m2M Ammonium Sulfate and 0.2M Lithium Nitrate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Oct 13, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 48047 / % possible obs: 100 % / Redundancy: 13.6 % / Biso Wilson estimate: 26.15 Å2 / Rmerge(I) obs: 0.102 / Χ2: 1.017 / Net I/av σ(I): 30.429 / Net I/σ(I): 8.4 / Num. measured all: 651706
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allDiffraction-ID% possible all
2.1-2.1412.80.4632372199.9
2.14-2.1812.90.389199.8
2.18-2.22130.3291100
2.22-2.2612.80.3261100
2.26-2.3113.20.2891100
2.31-2.3713.30.252199.7
2.37-2.4213.40.2231100
2.42-2.4913.30.2071100
2.49-2.5613.40.1811100
2.56-2.6513.50.1661100
2.65-2.7413.70.146199.9
2.74-2.8513.80.1321100
2.85-2.9813.90.1091100
2.98-3.1414.10.0961100
3.14-3.3314.20.0851100
3.33-3.5914.30.081100
3.59-3.95140.0741100
3.95-4.52140.0671100
4.52-5.714.20.0571100
5.7-5013.20.053199.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
BUSTER-TNT2.11.1refinement
HKL-2000data scaling
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
PHASERphasing
DENZOdata reduction
SCALEPACKdata scaling
BUSTERrefinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→49.09 Å / Cor.coef. Fo:Fc: 0.9379 / Cor.coef. Fo:Fc free: 0.9282 / SU R Cruickshank DPI: 0.149 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.153 / SU Rfree Blow DPI: 0.134 / SU Rfree Cruickshank DPI: 0.133
RfactorNum. reflection% reflectionSelection details
Rfree0.2084 2431 5.07 %RANDOM
Rwork0.185 ---
obs0.1862 47989 99.56 %-
Displacement parametersBiso max: 105.31 Å2 / Biso mean: 29.02 Å2 / Biso min: 8.07 Å2
Baniso -1Baniso -2Baniso -3
1-2.0612 Å20 Å20 Å2
2--2.0612 Å20 Å2
3----4.1224 Å2
Refine analyzeLuzzati coordinate error obs: 0.236 Å
Refinement stepCycle: final / Resolution: 2.1→49.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3930 0 247 263 4440
Biso mean--32.06 37.46 -
Num. residues----497
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1998SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes75HARMONIC2
X-RAY DIFFRACTIONt_gen_planes681HARMONIC5
X-RAY DIFFRACTIONt_it4278HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion553SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5207SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4278HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg5824HARMONIC21
X-RAY DIFFRACTIONt_omega_torsion3.41
X-RAY DIFFRACTIONt_other_torsion2.97
LS refinement shellResolution: 2.1→2.15 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2028 163 4.95 %
Rwork0.1719 3130 -
all0.1734 3293 -
obs--99.56 %
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)
12.33390.3688-0.24192.19540.54962.2173-0.01440.1198-0.0336-0.01570.04820.1147-0.01460.0305-0.0338-0.0538-0.0247-0.0064-0.05690.0049-0.0177-7.102223.445219.4995
22.0278-0.21260.0471.1949-0.3631.7842-0.0417-0.12050.01060.0209-0.0383-0.0044-0.07860.00570.08-0.03570.03250.0497-0.05450.00030.0113-11.044441.934337.1211
32.30320.41790.14151.2068-0.13261.4008-0.0263-0.05720.14360.0714-0.0361-0.04810.01510.02080.0624-0.03310.0105-0.0254-0.03230.0321-0.023713.240328.572538.9076
42.06680.56380.2792.7946-0.77141.9141-0.00950.18170.03410.0550.10950.05630.0019-0.0965-0.1001-0.0775-0.04710.0202-0.00440.0708-0.030810.184542.919116.9335
52.01040.23120.7181.41720.43551.63460.01250.0007-0.04060.07050.00210.01180.0491-0.0257-0.0146-0.0028-0.01110.02640.01040.0318-0.0916-11.316516.915250.9392
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|10 - 110}A10 - 110
2X-RAY DIFFRACTION2{B|10 - 112}B10 - 112
3X-RAY DIFFRACTION3{C|11 - 110}C11 - 110
4X-RAY DIFFRACTION4{D|10 - 110}D10 - 110
5X-RAY DIFFRACTION5{E|10 - 110}E10 - 110

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