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- PDB-8gjs: Stapled Peptide ALRN-6924 Bound to MDMX -

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Basic information

Entry
Database: PDB / ID: 8gjs
TitleStapled Peptide ALRN-6924 Bound to MDMX
Components
  • ACE-LEU-THR-PHE-ALA-GLU-TYR-TRP-ALA-GLN-LEU-DAL-ALA-ALA-ALA-ALA-ALA-DAL
  • Protein Mdm4
KeywordsAPOPTOSIS / Stapled Peptide Inhibitor Complex / MDMX
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 / 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 ...MDM4 / 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
Similarity search - Domain/homology
Biological speciesDanio rerio (zebrafish)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsGraves, B.J. / Janson, C. / Lukacs, C.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
F. Hoffmann-La Roche LTD Switzerland
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery of Sulanemadlin (ALRN-6924), the First Cell-Permeating, Stabilized alpha-Helical Peptide in Clinical Development.
Authors: Guerlavais, V. / Sawyer, T.K. / Carvajal, L. / Chang, Y.S. / Graves, B. / Ren, J.G. / Sutton, D. / Olson, K.A. / Packman, K. / Darlak, K. / Elkin, C. / Feyfant, E. / Kesavan, K. / Gangurde, ...Authors: Guerlavais, V. / Sawyer, T.K. / Carvajal, L. / Chang, Y.S. / Graves, B. / Ren, J.G. / Sutton, D. / Olson, K.A. / Packman, K. / Darlak, K. / Elkin, C. / Feyfant, E. / Kesavan, K. / Gangurde, P. / Vassilev, L.T. / Nash, H.M. / Vukovic, V. / Aivado, M. / Annis, D.A.
History
DepositionMar 16, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 26, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 9, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection / Derived calculations
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / struct_conn
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_label_atom_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Protein Mdm4
B: ACE-LEU-THR-PHE-ALA-GLU-TYR-TRP-ALA-GLN-LEU-DAL-ALA-ALA-ALA-ALA-ALA-DAL


Theoretical massNumber of molelcules
Total (without water)12,2412
Polymers12,2412
Non-polymers00
Water2,270126
1
A: Protein Mdm4


Theoretical massNumber of molelcules
Total (without water)10,3221
Polymers10,3221
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: ACE-LEU-THR-PHE-ALA-GLU-TYR-TRP-ALA-GLN-LEU-DAL-ALA-ALA-ALA-ALA-ALA-DAL


Theoretical massNumber of molelcules
Total (without water)1,9191
Polymers1,9191
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)81.513, 108.942, 31.434
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-212-

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
Source method: isolated from a genetically manipulated source
Details: The sequence is a humanized form of zebra fish MDM4 employing L46V and V95L mutations
Source: (gene. exp.) Danio rerio (zebrafish) / Gene: mdm4, mdmx / Plasmid: pET15B / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q7ZUW7
#2: Protein/peptide ACE-LEU-THR-PHE-ALA-GLU-TYR-TRP-ALA-GLN-LEU-DAL-ALA-ALA-ALA-ALA-ALA-DAL


Mass: 1919.265 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Danio rerio (zebrafish)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 126 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.85 Å3/Da / Density % sol: 56.85 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: PEG 4000,sodium chloride

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99997 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 30, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99997 Å / Relative weight: 1
ReflectionResolution: 1.56→33.17 Å / Num. obs: 20439 / % possible obs: 99.9 % / Redundancy: 6.3 % / Rpim(I) all: 0.024 / Rrim(I) all: 0.061 / Net I/σ(I): 14.4 / Num. measured all: 128319
Reflection shellResolution: 1.56→1.64 Å / % possible obs: 99.9 % / Redundancy: 6.2 % / Num. measured all: 18142 / Num. unique obs: 2917 / Rpim(I) all: 0.458 / Rrim(I) all: 1.148 / Net I/σ(I) obs: 1.7

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Processing

Software
NameClassification
SCALAdata scaling
CNXrefinement
HKL-2000data reduction
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.75→33.17 Å / Rfactor Rfree error: 0.008 / Data cutoff high absF: 1134104.06 / Data cutoff low absF: 0 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.217 736 5.1 %RANDOM
Rwork0.202 ---
obs0.203 14546 99.8 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 40.6727 Å2 / ksol: 0.33017 e/Å3
Displacement parametersBiso mean: 28 Å2
Baniso -1Baniso -2Baniso -3
1--0.76 Å20 Å20 Å2
2--1.03 Å20 Å2
3----0.27 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.23 Å0.21 Å
Luzzati d res low-5 Å
Luzzati sigma a0.18 Å0.15 Å
Refinement stepCycle: LAST / Resolution: 1.75→33.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms851 0 11 126 988
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.004
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg0.7
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d19.3
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.62
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.551.5
X-RAY DIFFRACTIONc_mcangle_it2.592
X-RAY DIFFRACTIONc_scbond_it2.242
X-RAY DIFFRACTIONc_scangle_it3.452.5
LS refinement shellResolution: 1.75→1.86 Å / Rfactor Rfree error: 0.031 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.342 118 5 %
Rwork0.299 2261 -
obs--99.7 %

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