[English] 日本語
Yorodumi
- PDB-5hmi: HDM2 in complex with a 3,3-Disubstituted Piperidine -

+
Open data


ID or keywords:

Loading...

-
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 / fibroblast activation / atrial septum development / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / negative regulation of signal transduction by p53 class mediator ...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 / fibroblast activation / atrial septum development / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / negative regulation of signal transduction by p53 class mediator / receptor serine/threonine kinase binding / Trafficking of AMPA receptors / peroxisome proliferator activated receptor binding / positive regulation of vascular associated smooth muscle cell migration / negative regulation of protein processing / SUMO transferase activity / response to iron ion / NEDD8 ligase activity / AKT phosphorylates targets in the cytosol / atrioventricular valve morphogenesis / cellular response to peptide hormone stimulus / response to steroid hormone / ventricular septum development / endocardial cushion morphogenesis / positive regulation of muscle cell differentiation / cellular response to alkaloid / SUMOylation of ubiquitinylation proteins / regulation of postsynaptic neurotransmitter receptor internalization / cardiac septum morphogenesis / blood vessel development / ligase activity / Constitutive Signaling by AKT1 E17K in Cancer / regulation of protein catabolic process / negative regulation of DNA damage response, signal transduction by p53 class mediator / response to magnesium ion / SUMOylation of transcription factors / protein sumoylation / cellular response to UV-C / cellular response to estrogen stimulus / blood vessel remodeling / cellular response to actinomycin D / protein localization to nucleus / ribonucleoprotein complex binding / protein autoubiquitination / positive regulation of vascular associated smooth muscle cell proliferation / NPAS4 regulates expression of target genes / transcription repressor complex / positive regulation of mitotic cell cycle / regulation of heart rate / DNA damage response, signal transduction by p53 class mediator / proteolysis involved in protein catabolic process / ubiquitin binding / positive regulation of protein export from nucleus / Stabilization of p53 / response to cocaine / establishment of protein localization / Regulation of RUNX3 expression and activity / cellular response to gamma radiation / protein destabilization / cellular response to growth factor stimulus / RING-type E3 ubiquitin transferase / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / centriolar satellite / cellular response to hydrogen peroxide / response to toxic substance / protein polyubiquitination / ubiquitin-protein transferase activity / disordered domain specific binding / p53 binding / endocytic vesicle membrane / ubiquitin protein ligase activity / Signaling by ALK fusions and activated point mutants / Regulation of TP53 Degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / negative regulation of neuron projection development / 5S rRNA binding / protein-containing complex assembly / ubiquitin-dependent protein catabolic process / Oxidative Stress Induced Senescence / cellular response to hypoxia / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of cell cycle / postsynaptic density / Ub-specific processing proteases / protein ubiquitination / protein domain specific binding / response to xenobiotic stimulus / response to antibiotic / negative regulation of DNA-templated transcription / apoptotic process / positive regulation of cell population proliferation / ubiquitin protein ligase binding / positive regulation of gene expression / negative regulation of apoptotic process / nucleolus / glutamatergic synapse / enzyme binding
Similarity search - Function
E3 ubiquitin-protein ligase Mdm2 / MDM2, modified RING finger, HC subclass / MDM2 / SWIB/MDM2 domain / 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 ...E3 ubiquitin-protein ligase Mdm2 / MDM2, modified RING finger, HC subclass / MDM2 / SWIB/MDM2 domain / 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 superfamily / Zinc finger RanBP2-type signature. / 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

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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

-
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


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


Mass: 18.015 Da / Num. of mol.: 108 / Source method: isolated from a natural source / Formula: H2O

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
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

-
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

-
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

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more