Systematic Mutational Analysis of Peptide Inhibition of the p53-MDM2/MDMX Interactions

Journal of Molecular Biology

Volumn 398, Issue 2, 2010, Pages 200-213

  Li, Chong ^a,b   Pazgier, Marzena ^a   Li, Changqing ^a   Yuan, Weirong ^a   Liu, Min ^a   Wei, Gang ^a,b   Lu, Wei Yue ^b   Lu, Wuyuan ^a  

^a UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

^b FUDAN UNIVERSITY   (China)

Author keywords

Alanine scanning mutagenesis; Crystallography; MDM2; MDMX; P53

Indexed keywords

ALANINE; ASPARTIC ACID; GLUTAMIC ACID; LEUCINE; PHENYLALANINE; PROLINE; PROTEIN INHIBITOR; PROTEIN MDM2; PROTEIN MDMX; PROTEIN P53; SERINE; THREONINE; TRYPTOPHAN;

ALPHA HELIX; ARTICLE; BINDING AFFINITY; BINDING COMPETITION; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG DESIGN; HYDROPHOBICITY; INHIBITION KINETICS; MALIGNANT NEOPLASTIC DISEASE; MOLECULAR INTERACTION; MOLECULAR MECHANICS; MUTATIONAL ANALYSIS; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN CONFORMATION; PROTEIN INTERACTION; QUANTITATIVE ANALYSIS;

EID: 77951766329     PISSN: 00222836     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.jmb.2010.03.005     Document Type: Article

References (58)

1. Vogelstein B., Lane D., Levine A.J. Surfing the p53 network. Nature 2000, 408:307-310.
2. Lane D.P. Cancer. p53, guardian of the genome. Nature 1992, 358:15-16.
3. Vousden K.H., Lane D.P. p53 in health and disease. Nat. Rev., Mol. Cell Biol. 2007, 8:275-283.
4. Martins C.P., Brown-Swigart L., Evan G.I. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 2006, 127:1323-1334.
5. Ventura A., Kirsch D.G., McLaughlin M.E., Tuveson D.A., Grimm J., Lintault L., et al. Restoration of p53 function leads to tumour regression in vivo. Nature 2007, 445:661-665.
6. Xue W., Zender L., Miething C., Dickins R.A., Hernando E., Krizhanovsky V., et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007, 445:656-660.
7. Brown C.J., Lain S., Verma C.S., Fersht A.R., Lane D.P. Awakening guardian angels: drugging the p53 pathway. Nat. Rev., Cancer 2009, 9:862-873.
8. Haupt Y., Maya R., Kazaz A., Oren M. Mdm2 promotes the rapid degradation of p53. Nature 1997, 387:296-299.
9. Honda R., Tanaka H., Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 1997, 420:25-27.
10. Kubbutat M.H., Jones S.N., Vousden K.H. Regulation of p53 stability by Mdm2. Nature 1997, 387:299-303.
11. Momand J., Zambetti G.P., Olson D.C., George D., Levine A.J. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 1992, 69:1237-1245.
12. Marine J.C., Dyer M.A., Jochemsen A.G. MDMX: from bench to bedside. J. Cell Sci. 2007, 120:371-378.
13. Toledo F., Wahl G.M. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat. Rev., Cancer 2006, 6:909-923.
14. de Graaf P., Little N.A., Ramos Y.F., Meulmeester E., Letteboer S.J., Jochemsen A.G. Hdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2. J. Biol. Chem. 2003, 278:38315-38324.
15. Linares L.K., Hengstermann A., Ciechanover A., Muller S., Scheffner M. HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53. Proc. Natl Acad. Sci. USA 2003, 100:12009-12014.
16. Pan Y., Chen J. MDM2 promotes ubiquitination and degradation of MDMX. Mol. Cell. Biol. 2003, 23:5113-5121.
17. Kussie P.H., Gorina S., Marechal V., Elenbaas B., Moreau J., Levine A.J., Pavletich N.P. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 1996, 274:948-953.
18. Popowicz G.M., Czarna A., Holak T.A. Structure of the human Mdmx protein bound to the p53 tumor suppressor transactivation domain. Cell Cycle 2008, 7:2441-2443.
19. Popowicz G.M., Czarna A., Rothweiler U., Sszwagierczak A., Krajewski M., Weber L., Holak T.A. Molecular basis for the inhibition of p53 by Mdmx. Cell Cycle 2007, 6:2386-2392.
20. Joerger A.C., Fersht A.R. Structural biology of the tumor suppressor p53. Annu. Rev. Biochem. 2008, 77:557-582.
21. Wells M., Tidow H., Rutherford T.J., Markwick P., Jensen M.R., Mylonas E., et al. Structure of tumor suppressor p53 and its intrinsically disordered N-terminal transactivation domain. Proc. Natl Acad. Sci. USA 2008, 105:5762-5767.
22. Bell S., Klein C., Muller L., Hansen S., Buchner J. p53 contains large unstructured regions in its native state. J. Mol. Biol. 2002, 322:917-927.
23. Schon O., Friedler A., Bycroft M., Freund S.M., Fersht A.R. Molecular mechanism of the interaction between MDM2 and p53. J. Mol. Biol. 2002, 323:491-501.
24. Bottger A., Bottger V., Garcia-Echeverria C., Chene P., Hochkeppel H.K., Sampson W., et al. Molecular characterization of the hdm2-p53 interaction. J. Mol. Biol. 1997, 269:744-756.
25. Lin J., Chen J., Elenbaas B., Levine A.J. Several hydrophobic amino acids in the p53 amino-terminal domain are required for transcriptional activation, binding to mdm-2 and the adenovirus 5 E1B 55-kD protein. Genes Dev. 1994, 8:1235-1246.
26. Massova I., Kollman P.A. Computational alanine scanning to probe protein-protein interactions: a novel approach to evaluate binding free energies. J. Am. Chem. Soc. 1999, 121:8133-8143.
27. Kortemme T., Baker D. A simple physical model for binding energy hot spots in protein-protein complexes. Proc. Natl Acad. Sci. USA 2002, 99:14116-14121.
28. Shangary S., Qin D., McEachern D., Liu M., Miller R.S., Qiu S., et al. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc. Natl Acad. Sci. USA 2008, 105:3933-3938.
29. Vassilev L.T., Vu B.T., Graves B., Carvajal D., Podlaski F., Filipovic Z., et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004, 303:844-848.
30. Kallen J., Goepfert A., Blechschmidt A., Izaac A., Geiser M., Tavares G., et al. Crystal structures of human MdmX (HdmX) in complex with p53 peptide analogues reveal surprising conformational changes. J. Biol. Chem. 2009, 284:8812-8821.
31. Reed D., Shen Y., Shelat A., Arnold A., Ferreira A., Zhu F., et al. Identification and characterization of the first small-molecule inhibitor of MDMX. J. Biol. Chem. 2010, Jan 15. [Epub ahead of print].
32. Hu B., Gilkes D.M., Chen J. Efficient p53 activation and apoptosis by simultaneous disruption of binding to MDM2 and MDMX. Cancer Res. 2007, 67:8810-8817.
33. Pazgier M., Liu M., Zou G., Yuan W., Li C., Li J., et al. Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX. Proc. Natl Acad. Sci. USA 2009, 106:4665-4670.
34. Li C., Liu M., Monbo J., Zou G., Yuan W., Zella D., et al. Turning a scorpion toxin into an antitumor miniprotein. J. Am. Chem. Soc. 2008, 130:13546-13548.
35. Li C., Pazgier M., Liu M., Lu W.Y., Lu W. Apamin as a template for structure-based rational design of potent peptide activators of p53. Angew. Chem., Int. Ed. Engl. 2009, 48:8712-8715.
36. Czarna A., Popowicz G.M., Pecak A., Wolf S., Dubin G., Holak T.A. High affinity interaction of the p53 peptide analogue with human Mdm2 and Mdmx. Cell Cycle 2009, 8:1176-1184.
37. Phan J., Li Z., Kasprzak A., Li B., Sebti S., Guida W., et al. Structure-based design of high-affinity peptides inhibiting the interaction of p53 with MDM2 and MDMX. J. Biol. Chem. 2010, 285:2174-2183.
38. Bottger V., Bottger A., Howard S.F., Picksley S.M., Chene P., Garcia-Echeverria C., et al. Identification of novel mdm2 binding peptides by phage display. Oncogene 1996, 13:2141-2147.
39. Chakrabartty A., Doig A.J., Baldwin R.L. Helix capping propensities in peptides parallel those in proteins. Proc. Natl Acad. Sci. USA 1993, 90:11332-11336.
40. Pace C.N., Scholtz J.M. A helix propensity scale based on experimental studies of peptides and proteins. Biophys. J. 1998, 75:422-427.
41. Brunger A.T. Free R value: a novel statistical quantity for assessing the accuracy of crystal structures. Nature 1992, 355:472-475.
42. Zondlo S.C., Lee A.E., Zondlo N.J. Determinants of specificity of MDM2 for the activation domains of p53 and p65: proline27 disrupts the MDM2-binding motif of p53. Biochemistry 2006, 45:11945-11957.
43. Kalid O., Ben-Tal N. Study of MDM2 binding to p53-analogues: affinity, helicity, and applicability to drug design. J. Chem. Inf. Model. 2009, 49:865-876.
44. Lai Z., Auger K.R., Manubay C.M., Copeland R.A. Thermodynamics of p53 binding to hdm2(1-126): effects of phosphorylation and p53 peptide length. Arch. Biochem. Biophys. 2000, 381:278-284.
45. Lee H.J., Srinivasan D., Coomber D., Lane D.P., Verma C.S. Modulation of the p53-MDM2 interaction by phosphorylation of Thr18: a computational study. Cell Cycle 2007, 6:2604-2611.
46. Dastidar S.G., Lane D.P., Verma C.S. Multiple peptide conformations give rise to similar binding affinities: molecular simulations of p53-MDM2. J. Am. Chem. Soc. 2008, 130:13514-13515.
47. Laskowski M., Qasim M.A., Yi Z. Additivity-based prediction of equilibrium constants for some protein-protein associations. Curr. Opin. Struct. Biol. 2003, 13:130-139.
48. Qasim M.A., Ganz P.J., Saunders C.W., Bateman K.S., James M.N., Laskowski M. Interscaffolding additivity. Association of P1 variants of eglin c and of turkey ovomucoid third domain with serine proteinases. Biochemistry 1997, 36:1598-1607.
49. Bottger V., Bottger A., Garcia-Echeverria C., Ramos Y.F., van der Eb A.J., Jochemsen A.G., Lane D.P. Comparative study of the p53-mdm2 and p53-MDMX interfaces. Oncogene 1999, 18:189-199.
50. Santamaria F., Wu Z., Boulegue C., Pal G., Lu W. Reexamination of the recognition preference of the specificity pocket of the Abl SH3 domain. J. Mol. Recognit. 2003, 16:131-138.
51. Scheidig A.J., Hynes T.R., Pelletier L.A., Wells J.A., Kossiakoff A.A. Crystal structures of bovine chymotrypsin and trypsin complexed to the inhibitor domain of Alzheimer's amyloid beta-protein precursor (APPI) and basic pancreatic trypsin inhibitor (BPTI): engineering of inhibitors with altered specificities. Protein Sci. 1997, 6:1806-1824.
52. Zhong H., Carlson H.A. Computational studies and peptidomimetic design for the human p53-MDM2 complex. Proteins 2005, 58:222-234.
53. Schnolzer M., Alewood P., Jones A., Alewood D., Kent S.B. In situ neutralization in Boc-chemistry solid phase peptide synthesis. Rapid, high yield assembly of difficult sequences. Int. J. Pept. Protein Res. 1992, 40:180-193.
54. Pace C.N., Vajdos F., Fee L., Grimsley G., Gray T. How to measure and predict the molar absorption coefficient of a protein. Protein Sci. 1995, 4:2411-2423.
55. Methods in Enzymology 1997, Academic Press, San Diego, London. Z. Otwinowski, W. Minor, C.W. Carter (Eds.).
56. Storoni L.C., McCoy A.J., Read R.J. Likelihood-enhanced fast rotation functions. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004, 60:432-438.
57. Murshudov G.N., Vagin A.A., Dodson E.J. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr., Sect. D: Biol. Crystallogr. 1997, 53:240-255.
58. Emsley P., Cowtan K. Coot: model-building tools for molecular graphics. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004, 60:2126-2132.