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- PDB-4hbm: Ordering of the N Terminus of Human MDM2 by Small Molecule Inhibitors -

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Basic information

Entry
Database: PDB / ID: 4hbm
TitleOrdering of the N Terminus of Human MDM2 by Small Molecule Inhibitors
ComponentsE3 ubiquitin-protein ligase Mdm2
Keywordsligase/ligase inhibitor / MDM2 / p53 / protein protein interaction / 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 / 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 / SUMO transferase activity / response to steroid hormone / 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 / blood vessel remodeling / cellular response to estrogen stimulus / protein autoubiquitination / 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 / 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 / cellular response to gamma radiation / 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 / negative regulation of neuron projection development / p53 binding / 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-0Y7 / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsHuang, X.
CitationJournal: J.Am.Chem.Soc. / Year: 2012
Title: Ordering of the N-terminus of human MDM2 by small molecule inhibitors.
Authors: Michelsen, K. / Jordan, J.B. / Lewis, J. / Long, A.M. / Yang, E. / Rew, Y. / Zhou, J. / Yakowec, P. / Schnier, P.D. / Huang, X. / Poppe, L.
History
DepositionSep 28, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 17, 2012Provider: repository / Type: Initial release
Revision 1.1Jan 2, 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_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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

Downloads & links

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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
F: E3 ubiquitin-protein ligase Mdm2
G: E3 ubiquitin-protein ligase Mdm2
H: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,36716
Polymers108,7648
Non-polymers3,6038
Water15,601866
1
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,0462
Polymers13,5961
Non-polymers4501
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,0462
Polymers13,5961
Non-polymers4501
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,0462
Polymers13,5961
Non-polymers4501
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,0462
Polymers13,5961
Non-polymers4501
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
E: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,0462
Polymers13,5961
Non-polymers4501
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
F: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,0462
Polymers13,5961
Non-polymers4501
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
7
G: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,0462
Polymers13,5961
Non-polymers4501
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
8
H: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,0462
Polymers13,5961
Non-polymers4501
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
9
A: E3 ubiquitin-protein ligase Mdm2
B: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,0924
Polymers27,1912
Non-polymers9012
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1280 Å2
ΔGint-7 kcal/mol
Surface area10610 Å2
MethodPISA
10
C: E3 ubiquitin-protein ligase Mdm2
hetero molecules

E: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,0924
Polymers27,1912
Non-polymers9012
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_545-x,y-1,-z1
Buried area1350 Å2
ΔGint-3 kcal/mol
Surface area10200 Å2
MethodPISA
11
D: E3 ubiquitin-protein ligase Mdm2
hetero molecules

F: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,0924
Polymers27,1912
Non-polymers9012
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555-x+1/2,y+1/2,-z1
Buried area1230 Å2
ΔGint-5 kcal/mol
Surface area9940 Å2
MethodPISA
12
G: E3 ubiquitin-protein ligase Mdm2
hetero molecules

H: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,0924
Polymers27,1912
Non-polymers9012
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_546-x+1/2,y-1/2,-z+11
Buried area1150 Å2
ΔGint-5 kcal/mol
Surface area9800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)185.35, 73.95, 123.09
Angle α, β, γ (deg.)90, 121.60, 90
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 13595.528 Da / Num. of mol.: 8
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-0Y7 / {(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2S)-1-hydroxybutan-2-yl]-2-oxopiperidin-3-yl}acetic acid


Mass: 450.355 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C23H25Cl2NO4
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 866 / 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: 3.3 Å3/Da / Density % sol: 62.76 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 100 mM Citrate, pH 5.0 1.5-2.0 M (NH4)2SO4 , 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
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 1.9→50 Å / Num. all: 109869 / Num. obs: 413436 / % possible obs: 98.6 % / Observed criterion σ(I): -3 / Rmerge(I) obs: 0.057
Reflection shellResolution: 1.9→1.97 Å / Rmerge(I) obs: 0.493 / % possible all: 97.6

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Processing

Software
NameClassification
HKL-2000data collection
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→50 Å / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.24 5485 RANDOM
Rwork0.22 --
obs-109867 -
Refinement stepCycle: LAST / Resolution: 1.9→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6483 0 240 866 7589

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