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- PDB-5hmi: HDM2 in complex with a 3,3-Disubstituted Piperidine -

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Basic information

Entry
Database: PDB / ID: 5hmi
TitleHDM2 in complex with a 3,3-Disubstituted Piperidine
ComponentsE3 ubiquitin-protein ligase Mdm2
Keywordsligase/ligase inhibitor / Oncology / E3 ubiquitin-protein ligase / p53/TP53 / 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 / response to iron ion / negative regulation of protein processing / SUMO transferase activity / 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 / protein sumoylation / SUMOylation of transcription factors / 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 / proteolysis involved in protein catabolic process / positive regulation of protein export from nucleus / response to cocaine / ubiquitin binding / Stabilization of p53 / Regulation of RUNX3 expression and activity / protein destabilization / RING-type E3 ubiquitin transferase / Signaling by ALK fusions and activated point mutants / establishment of protein localization / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / cellular response to gamma radiation / response to toxic substance / 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 / Regulation of TP53 Degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / p53 binding / negative regulation of neuron projection development / 5S rRNA binding / cellular response to hypoxia / ubiquitin-dependent protein catabolic process / regulation of gene expression / proteasome-mediated ubiquitin-dependent protein catabolic process / protein-containing complex assembly / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / Ub-specific processing proteases / protein ubiquitination / regulation of cell cycle / 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
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-62T / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.74 Å
AuthorsScapin, G.
CitationJournal: Acs Med.Chem.Lett. / Year: 2016
Title: Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors.
Authors: Bogen, S.L. / Pan, W. / Gibeau, C.R. / Lahue, B.R. / Ma, Y. / Nair, L.G. / Seigel, E. / Shipps, G.W. / Tian, Y. / Wang, Y. / Lin, Y. / Liu, M. / Liu, S. / Mirza, A. / Wang, X. / Lipari, P. / ...Authors: Bogen, S.L. / Pan, W. / Gibeau, C.R. / Lahue, B.R. / Ma, Y. / Nair, L.G. / Seigel, E. / Shipps, G.W. / Tian, Y. / Wang, Y. / Lin, Y. / Liu, M. / Liu, S. / Mirza, A. / Wang, X. / Lipari, P. / Seidel-Dugan, C. / Hicklin, D.J. / Bishop, W.R. / Rindgen, D. / Nomeir, A. / Prosise, W. / Reichert, P. / Scapin, G. / Strickland, C. / Doll, R.J.
History
DepositionJan 16, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 6, 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
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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,5315
Polymers24,0062
Non-polymers1,5253
Water1,946108
1
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,8143
Polymers12,0031
Non-polymers8112
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)12,7182
Polymers12,0031
Non-polymers7151
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1320 Å2
ΔGint-2 kcal/mol
Surface area11350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.473, 38.915, 132.505
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 12002.915 Da / Num. of mol.: 2 / Mutation: F55Y, Y76H
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-62T / {4-[2-(2-hydroxyethoxy)phenyl]piperazin-1-yl}[(2R,3S)-2-propyl-1-{[4-(trifluoromethyl)pyridin-3-yl]carbonyl}-3-{[5-(trifluoromethyl)thiophen-3-yl]oxy}piperidin-3-yl]methanone


Mass: 714.718 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H36F6N4O5S
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 108 / 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: 2.21 Å3/Da / Density % sol: 44.39 %
Crystal growTemperature: 303 K / Method: vapor diffusion, sitting drop / pH: 4.2
Details: 1.8-2.2 M ammonium sulfate, 100 mM NaCitrate/Citric acid

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 5, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.74→44.17 Å / Num. obs: 21845 / % possible obs: 100 % / Redundancy: 6.3 % / Biso Wilson estimate: 36.15 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.035 / Rpim(I) all: 0.015 / Net I/σ(I): 22.6 / Num. measured all: 137686
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
1.74-1.946.40.35141100
3.89-44.175.70.02653.5199.6

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Processing

Software
NameVersionClassification
d*TREKdata scaling
Aimless0.3.6data scaling
BUSTER-TNTBUSTER 2.11.5refinement
PDB_EXTRACT3.15data extraction
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.74→37.34 Å / Cor.coef. Fo:Fc: 0.9521 / Cor.coef. Fo:Fc free: 0.9472 / SU R Cruickshank DPI: 0.126 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.13 / SU Rfree Blow DPI: 0.116 / SU Rfree Cruickshank DPI: 0.114
RfactorNum. reflection% reflectionSelection details
Rfree0.2289 1103 5.07 %RANDOM
Rwork0.2076 ---
obs0.2087 21742 99.93 %-
Displacement parametersBiso max: 138.67 Å2 / Biso mean: 52.9 Å2 / Biso min: 25.34 Å2
Baniso -1Baniso -2Baniso -3
1-2.4609 Å20 Å20 Å2
2---3.6896 Å20 Å2
3---1.2287 Å2
Refine analyzeLuzzati coordinate error obs: 0.42 Å
Refinement stepCycle: final / Resolution: 1.74→37.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1573 0 103 108 1784
Biso mean--47.7 56.39 -
Num. residues----196
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d627SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes34HARMONIC2
X-RAY DIFFRACTIONt_gen_planes280HARMONIC5
X-RAY DIFFRACTIONt_it1719HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion211SEMIHARMONIC5
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_contact2077SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1719HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2336HARMONIC21.19
X-RAY DIFFRACTIONt_omega_torsion3.34
X-RAY DIFFRACTIONt_other_torsion18.57
LS refinement shellResolution: 1.74→1.82 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2721 130 4.6 %
Rwork0.2093 2698 -
all0.2121 2828 -
obs--99.93 %
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)
13.79811.37112.09081.56721.10813.5039-0.12230.61490.1303-0.02560.08780.0406-0.00040.5220.03440.00850.0112-0.00310.00220.0542-0.0611-14.636-1.89525.988
21.87931.07410.67441.68610.04993.03860.11860.077-0.05590.1773-0.09830.01740.17710.2321-0.0203-0.37190.01880.00840.50160.156-0.3101-6.2775.3327.131
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|18 - A|113 A|1001 - A|1001 }A18 - 113
2X-RAY DIFFRACTION1{ A|18 - A|113 A|1001 - A|1001 }A1001
3X-RAY DIFFRACTION2{ B|20 - B|119 B|1001 - B|1001 }B20 - 119
4X-RAY DIFFRACTION2{ B|20 - B|119 B|1001 - B|1001 }B1001

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