3LNZ

Crystal structure of human MDM2 with a 12-mer peptide inhibitor PMI (N8A mutant)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.222 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Systematic mutational analysis of peptide inhibition of the p53-MDM2/MDMX interactions.

Li, C.Pazgier, M.Li, C.Yuan, W.Liu, M.Wei, G.Lu, W.Y.Lu, W.

(2010) J Mol Biol 398: 200-213

  • DOI: https://doi.org/10.1016/j.jmb.2010.03.005
  • Primary Citation of Related Structures:  
    3LNZ

  • PubMed Abstract: 

    Inhibition of the interaction between the tumor suppressor protein p53 and its negative regulators MDM2 and MDMX is of great interest in cancer biology and drug design. We previously reported a potent duodecimal peptide inhibitor, termed PMI (TSFAEYWNLLSP), of the p53-MDM2 and -MDMX interactions. PMI competes with p53 for MDM2 and MDMX binding at an affinity roughly 2 orders of magnitude higher than that of (17-28)p53 (ETFSDLWKLLPE) of the same length; both peptides adopt nearly identical alpha-helical conformations in the complexes, where the three highlighted hydrophobic residues Phe, Trp, and Leu dominate PMI or (17-28)p53 binding to MDM2 and MDMX. To elucidate the molecular determinants for PMI activity and specificity, we performed a systematic Ala scanning mutational analysis of PMI and (17-28)p53. The binding affinities for MDM2 and MDMX of a total of 35 peptides including 10 truncation analogs were quantified, affording a complete dissection of energetic contributions of individual residues of PMI and (17-28)p53 to MDM2 and MDMX association. Importantly, the N8A mutation turned PMI into the most potent dual-specific antagonist of MDM2 and MDMX reported to date, registering respective K(d) values of 490 pM and 2.4 nM. The co-crystal structure of N8A-PMI-(25-109)MDM2 was determined at 1.95 A, affirming that high-affinity peptide binding to MDM2/MDMX necessitates, in addition to optimized intermolecular interactions, enhanced helix stability or propensity contributed by non-contact residues. The powerful empirical binding data and crystal structures present a unique opportunity for computational studies of peptide inhibition of the p53-MDM2/MDMX interactions.


  • Organizational Affiliation

    Institute of Human Virology, University of Maryland School of Medicine, 725 West Lombard Street, Baltimore, MD 21201, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
E3 ubiquitin-protein ligase Mdm2
A, C, E, G, I
A, C, E, G, I, K, M, O
85N/AMutation(s): 0 
EC: 6.3.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q00987 (Homo sapiens)
Explore Q00987 
Go to UniProtKB:  Q00987
PHAROS:  Q00987
GTEx:  ENSG00000135679 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ00987
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
12-mer peptide inhibitor
B, D, F, H, J
B, D, F, H, J, L, N, P
12N/AMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.222 
  • Space Group: P 32 1 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 90.544α = 90
b = 90.544β = 90
c = 196.837γ = 120
Software Package:
Software NamePurpose
HKL-2000data collection
PHASERphasing
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-03-09
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.2: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description