NMR structure of a complex between MDM2 and a small molecule inhibitor

被引:64
作者
Fry, DC
Emerson, SD
Palme, S
Vu, BT
Liu, CM
Podlaski, F
机构
[1] Hoffmann La Roche Inc, Roche Res Ctr, Nutley, NJ 07110 USA
[2] Roche Diagnost GmbH, Pharma Res, D-82377 Penzberg, Germany
关键词
MDM2; NMR spectroscopy; protein-protein interaction; protein structure;
D O I
10.1023/B:JNMR.0000048856.84603.9b
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
MDM2 is a regulator of cell growth processes that acts by binding to the tumor suppressor protein p53 and ultimately restraining its activity. While inactivation of p53 by mutation is commonly observed in human cancers, a substantial percentage of tumors express wild type p53. In many of these cases, MDM2 is overexpressed, and it is believed that suppression of MDM2 activity could yield therapeutic benefits. Therefore, we have been focusing on the p53-MDM2 interaction as the basis of a drug discovery program and have been able to develop a series of small molecule inhibitors. We herein report a high resolution NMR structure of a complex between the p53-binding domain of MDM2 and one of these inhibitors. The form of MDM2 utilized was an engineered hybrid between the human and Xenopus sequences, which provided a favorable combination of relevancy and stability. The inhibitor is found to bind in the same site as does a highly potent peptide fragment of p53. The inhibitor is able to successfully mimic the peptide by duplicating interactions in three subpockets normally made by amino acid sidechains, and by utilizing a scaffold that presents substituents with rigidity and spatial orientation comparable to that provided by the alpha helical backbone of the peptide. The structure also suggests opportunities for modifying the inhibitor to increase its potency.
引用
收藏
页码:163 / 173
页数:11
相关论文
共 61 条
  • [51] A view to a kill: ligands for Bcl-2 family proteins
    Rutledge, SE
    Chin, JW
    Schepartz, A
    [J]. CURRENT OPINION IN CHEMICAL BIOLOGY, 2002, 6 (04) : 479 - 485
  • [52] ITERATIVE SCHEMES FOR BILINEAR OPERATORS - APPLICATION TO SPIN DECOUPLING
    SHAKA, AJ
    LEE, CJ
    PINES, A
    [J]. JOURNAL OF MAGNETIC RESONANCE, 1988, 77 (02): : 274 - 293
  • [53] Shibagaki I, 1995, CLIN CANCER RES, V1, P769
  • [54] An orally bioavailable pyrrolinone inhibitor of HIV-1 protease: Computational analysis and x-ray crystal structure of the enzyme complex
    Smith, AB
    Hirschmann, R
    Pasternak, A
    Yao, WQ
    Sprengeler, PA
    Holloway, MK
    Kuo, LC
    Chen, ZG
    Darke, PL
    Schleif, WA
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1997, 40 (16) : 2440 - 2444
  • [55] Chalcone derivatives antagonize interactions between the human oncoprotein MDM2 and p53
    Stoll, R
    Renner, C
    Hansen, S
    Palme, S
    Klein, C
    Belling, A
    Zeslawski, W
    Kamionka, M
    Rehm, T
    Mühlhahn, P
    Schumacher, R
    Hesse, F
    Kaluza, B
    Voelter, W
    Engh, RA
    Holak, TA
    [J]. BIOCHEMISTRY, 2001, 40 (02) : 336 - 344
  • [56] MINIMIZING SENSITIVITY LOSSES IN GRADIENT-SELECTED N-15-H-1 HSQC SPECTRA OF PROTEINS
    STONEHOUSE, J
    SHAW, GL
    KEELER, J
    LAUE, ED
    [J]. JOURNAL OF MAGNETIC RESONANCE SERIES A, 1994, 107 (02) : 178 - 184
  • [57] Identification of a small molecule inhibitor of the IL-2/IL-2R alpha receptor interaction which binds to IL-2
    Tilley, JW
    Chen, L
    Fry, DC
    Emerson, SD
    Powers, GD
    Biondi, D
    Varnell, T
    Trilles, R
    Guthrie, R
    Mennona, F
    Kaplan, G
    LeMahieu, RA
    Carson, M
    Han, RJ
    Liu, CM
    Palermo, R
    Ju, G
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1997, 119 (32) : 7589 - 7590
  • [58] Inhibition of protein-protein association by small molecules: Approaches and progress
    Toogood, PL
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (08) : 1543 - 1558
  • [59] DIAZA-COPE-REARRANGEMENT
    VOGTLE, F
    GOLDSCHMITT, E
    [J]. CHEMISCHE BERICHTE-RECUEIL, 1976, 109 (01): : 1 - 40
  • [60] The p53-Mdm2 Pathway: Targets for the Development of New Anticancer Therapeutics
    Zheleva, Daniella I.
    Lane, David P.
    Fischer, Peter M.
    [J]. MINI-REVIEWS IN MEDICINAL CHEMISTRY, 2003, 3 (03) : 257 - 270