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- PDB-4n5t: The 1.7A Crystal Structure of MDMX with a Stapled Peptide, ATSP-7041 -

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Basic information

Entry
Database: PDB / ID: 4n5t
TitleThe 1.7A Crystal Structure of MDMX with a Stapled Peptide, ATSP-7041
Components
  • ATSP-7041 stapled-peptide
  • Protein Mdm4
KeywordsCELL CYCLE/CELL CYCLE INHIBITOR / MDM4 / p53 / apoptosis / cell cycle / p53 antagonist / nucleus / CELL CYCLE-CELL CYCLE INHIBITOR complex
Function / homology
Function and homology information


Oxidative Stress Induced Senescence / Oncogene Induced Senescence / Regulation of TP53 Degradation / Stabilization of p53 / ubiquitin-protein transferase activity / regulation of cell cycle / protein ubiquitination / negative regulation of apoptotic process / nucleus / metal ion binding
Similarity search - Function
MDM4 / MDM2 / SWIB/MDM2 domain / p53 negative regulator Mdm2/Mdm4 / SWIB/MDM2 domain / SWIB/MDM2 domain / SWIB/MDM2 domain profile. / SWIB/MDM2 domain superfamily / Zinc finger, C3HC4 type (RING finger) / Zinc finger RanBP2 type profile. ...MDM4 / MDM2 / SWIB/MDM2 domain / p53 negative regulator Mdm2/Mdm4 / SWIB/MDM2 domain / SWIB/MDM2 domain / SWIB/MDM2 domain profile. / SWIB/MDM2 domain superfamily / 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/FYVE/PHD-type / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
ATSP-7041 stapled-peptide / Protein Mdm4
Similarity search - Component
Biological speciesDanio rerio (zebrafish)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsGraves, B.J. / Lukacs, C. / Janson, C.A.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2013
Title: Stapled alpha-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy.
Authors: Chang, Y.S. / Graves, B. / Guerlavais, V. / Tovar, C. / Packman, K. / To, K.H. / Olson, K.A. / Kesavan, K. / Gangurde, P. / Mukherjee, A. / Baker, T. / Darlak, K. / Elkin, C. / Filipovic, Z. ...Authors: Chang, Y.S. / Graves, B. / Guerlavais, V. / Tovar, C. / Packman, K. / To, K.H. / Olson, K.A. / Kesavan, K. / Gangurde, P. / Mukherjee, A. / Baker, T. / Darlak, K. / Elkin, C. / Filipovic, Z. / Qureshi, F.Z. / Cai, H. / Berry, P. / Feyfant, E. / Shi, X.E. / Horstick, J. / Annis, D.A. / Manning, A.M. / Fotouhi, N. / Nash, H. / Vassilev, L.T. / Sawyer, T.K.
History
DepositionOct 10, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 20, 2013Provider: repository / Type: Initial release
Revision 1.1Nov 15, 2017Group: Refinement description / Category: software
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / database_2 / struct_conn / struct_ref_seq_dif / struct_site
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_value_order / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _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

Downloads & links

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Assembly

Deposited unit
A: Protein Mdm4
B: ATSP-7041 stapled-peptide


Theoretical massNumber of molelcules
Total (without water)12,0562
Polymers12,0562
Non-polymers00
Water2,252125
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1360 Å2
ΔGint-10 kcal/mol
Surface area5530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.585, 108.535, 30.964
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-243-

HOH

21A-284-

HOH

31A-295-

HOH

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Components

#1: Protein Protein Mdm4 / Double minute 4 protein / Mdm2-like p53-binding protein / Protein Mdmx / p53-binding protein Mdm4


Mass: 10322.081 Da / Num. of mol.: 1 / Fragment: SWIB Domain (UNP Residues 15-106) / Mutation: L46V, V95L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Danio rerio (zebrafish) / Gene: mdm4, mdmx / Plasmid: pET15b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q7ZUW7
#2: Protein/peptide ATSP-7041 stapled-peptide


Type: Peptide-like / Class: Enzyme inhibitor / Mass: 1734.042 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: ATSP-7041 was chemically synthesized and is loosely based on a sequence from p53
Source: (synth.) synthetic construct (others) / References: ATSP-7041 stapled-peptide
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 125 / 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: 2.78 Å3/Da / Density % sol: 55.82 %
Crystal growTemperature: 278 K / Method: vapor diffusion, sitting drop / pH: 5.6
Details: 15% PEG 4000, 0.1M sodium citrate, 0.2M ammonium sulfate, pH 5.6, VAPOR DIFFUSION, SITTING DROP, temperature 278K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9998 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Jul 9, 2011
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9998 Å / Relative weight: 1
ReflectionResolution: 1.47→40.79 Å / Num. all: 23886 / Num. obs: 23886 / % possible obs: 99.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 6.4 % / Biso Wilson estimate: 26.3 Å2 / Rmerge(I) obs: 0.046 / Net I/σ(I): 15.5
Reflection shellResolution: 1.47→1.55 Å / % possible all: 99.9

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Processing

Software
NameVersionClassification
DA+data collection
MOLREPphasing
CNX2005refinement
XDSdata reduction
SCALAdata scaling
TRUNCATEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→33.07 Å / Rfactor Rfree error: 0.008 / Data cutoff high absF: 1652927.99 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.228 799 5.1 %RANDOM
Rwork0.209 ---
all0.21 15537 --
obs0.21 15537 99.5 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 46.3115 Å2 / ksol: 0.331126 e/Å3
Displacement parametersBiso mean: 32.4 Å2
Baniso -1Baniso -2Baniso -3
1--2.56 Å20 Å20 Å2
2--4.06 Å20 Å2
3----1.5 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.22 Å0.21 Å
Luzzati d res low-5 Å
Luzzati sigma a0.15 Å0.15 Å
Refinement stepCycle: LAST / Resolution: 1.7→33.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms849 0 0 125 974
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.004
X-RAY DIFFRACTIONc_angle_deg1.6
X-RAY DIFFRACTIONc_dihedral_angle_d18.7
X-RAY DIFFRACTIONc_improper_angle_d0.65
X-RAY DIFFRACTIONc_mcbond_it1.471.5
X-RAY DIFFRACTIONc_mcangle_it2.412
X-RAY DIFFRACTIONc_scbond_it2.242
X-RAY DIFFRACTIONc_scangle_it3.492.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 1.7→1.81 Å / Rfactor Rfree error: 0.027 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.311 133 5.2 %
Rwork0.28 2408 -
obs--99.8 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2carbohydrate.parcarbohydrate.top
X-RAY DIFFRACTION3water_rep.paramwater.top
X-RAY DIFFRACTION4ion.paramion.top
X-RAY DIFFRACTION56101-sp1.prx6101-sp1.tpx

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