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- PDB-3w69: Crystal structure of human mdm2 with a dihydroimidazothiazole inh... -

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Basic information

Entry
Database: PDB / ID: 3w69
TitleCrystal structure of human mdm2 with a dihydroimidazothiazole inhibitor
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE/LIGASE INHIBITOR / Ubiquitin-protein ligase E3 Mdm2 / p53 / 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-LTZ / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsShimizu, H. / Katakura, S. / Miyazaki, M. / Naito, H. / Sugimoto, Y. / Kawato, H. / Okayama, T. / Soga, T.
CitationJournal: Bioorg.Med.Chem. / Year: 2013
Title: Synthesis and evaluation of novel orally active p53-MDM2 interaction inhibitors
Authors: Miyazaki, M. / Naito, H. / Sugimoto, Y. / Yoshida, K. / Kawato, H. / Okayama, T. / Shimizu, H. / Miyazaki, M. / Kitagawa, M. / Seki, T. / Fukutake, S. / Shiose, Y. / Aonuma, M. / Soga, T.
History
DepositionFeb 12, 2013Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 5, 2013Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2014Group: Database references
Revision 1.2Nov 8, 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_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
B: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0927
Polymers20,4102
Non-polymers1,6825
Water2,432135
1
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)10,9983
Polymers10,2051
Non-polymers7932
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)11,0944
Polymers10,2051
Non-polymers8893
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)53.562, 65.761, 81.436
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 10204.974 Da / Num. of mol.: 2 / Fragment: UNP residues 25-109 / Mutation: L33E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Plasmid: pGEX4T3 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21
References: UniProt: Q00987, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Chemical ChemComp-LTZ / (5R,6S)-2-[((2S,5R)-2-{[(3R)-4-acetyl-3-methylpiperazin-1-yl]carbonyl}-5-ethylpyrrolidin-1-yl)carbonyl]-5,6-bis(4-chlorophenyl)-3-isopropyl-6-methyl-5,6-dihydroimidazo[2,1-b][1,3]thiazole


Mass: 696.729 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C36H43Cl2N5O3S
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 135 / 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: 3.51 Å3/Da / Density % sol: 64.99 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.1
Details: 2.4M Ammonium sulfate, 5% PEG 200, 0.1M Tris HCl, pH 8.1 , VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54178 Å
DetectorType: RIGAKU RAXIS VII / Detector: IMAGE PLATE / Date: Mar 2, 2007 / Details: confocal mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.9→44.8 Å / Num. all: 22427 / Num. obs: 22162 / % possible obs: 95.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 2.1 % / Rmerge(I) obs: 0.069 / Net I/σ(I): 8.3
Reflection shellResolution: 1.9→2 Å / Redundancy: 2 % / Rmerge(I) obs: 0.475 / Mean I/σ(I) obs: 1.5 / Num. unique all: 2930 / % possible all: 95.2

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.2.0019refinement
PROCESSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1RV1

1rv1


Resolution: 1.9→21.18 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.93 / SU B: 3.658 / SU ML: 0.104 / Cross valid method: THROUGHOUT / ESU R: 0.137 / ESU R Free: 0.129 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2381 1079 4.9 %RANDOM
Rwork0.20894 ---
obs0.21038 20969 100 %-
all-22162 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 30.626 Å2
Baniso -1Baniso -2Baniso -3
1-1.23 Å20 Å20 Å2
2--0.19 Å20 Å2
3----1.42 Å2
Refinement stepCycle: LAST / Resolution: 1.9→21.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1414 0 109 135 1658
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0221558
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.1272.0812118
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5825168
X-RAY DIFFRACTIONr_dihedral_angle_2_deg42.5923.54862
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.48615286
X-RAY DIFFRACTIONr_dihedral_angle_4_deg25.888158
X-RAY DIFFRACTIONr_chiral_restr0.1030.2232
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021140
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2190.2735
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3170.21084
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1550.2113
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1960.236
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1970.215
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8671.5872
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.55521384
X-RAY DIFFRACTIONr_scbond_it2.0763787
X-RAY DIFFRACTIONr_scangle_it3.2924.5734
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.405 87 -
Rwork0.317 1487 -
obs--100 %

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