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Modulation of p53 binding to MDM2: computational studies reveal important roles of Tyr100

Modulation of p53 binding to MDM2: computational studies reveal important roles of Tyr100. Shubhra G Dastidar , David P Lane, Chandra S Verma. p53 network. Vogelstein, B., Lane, D. P., and Levine, A. J. (2000). Surfing the p53 network. Nature 408: 307-310. Transactivation domain of p53: 17-29

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Modulation of p53 binding to MDM2: computational studies reveal important roles of Tyr100

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  1. Modulation of p53 binding to MDM2: computational studies reveal important roles of Tyr100 Shubhra G Dastidar, David P Lane, Chandra S Verma

  2. p53 network Vogelstein, B., Lane, D. P., and Levine, A. J. (2000). Surfing the p53 network. Nature 408: 307-310.

  3. Transactivation domain of p53: 17-29 MDM2: 25-109 Kussie et al., Science 1996 Vassilev et al., Science 2004

  4. L26 F19 W23 • P27S mutation ΔΔG = -2.3kcal/mol P27 E17TFSD LWKLL PEN29 Zondlo et al. Biochemistry 2006

  5. S27 S27 Crystallographically observed binding mode of WT is retained ΔΔG = -4.2 kcal/mol Δ ΔH= -0.8 -T ΔΔS = -3.4 ΔΔG = -4.2 α-helix is propagated by another turn ΔΔ G= -4.7 kcal/mol ΔΔH= -3.6 -T ΔΔS= -1.1 ΔΔG= -4.7 Dastidar, S.G., Lane D.P., Verma C.S., J. Am. Chem. Soc. 2008

  6. Ligand with extended C-terminus Ligand with helical conformation Y100 orients as in wild type Y100 flips in Dastidar, S.G., Lane D.P., Verma C.S., J. Am. Chem. Soc. 2008

  7. Modulation of binding site of MDM2 while binding to a variety of ligands in PDB p53 Nutlin Optimized peptide β-hairpin IC50 ~ 10-2000nM Optimized peptide 12/1 peptide

  8. L26 Y100

  9. Y100

  10. E17 K70 E28 R65 K51

  11. K70 K94 R97 Y100 K51

  12. K94 R97 K51

  13. p53 binding pocket Apo After MD in presence of p53

  14. N-terminal lid Y100 p53 binding pocket C-terminal end, connects other domains of MDM2

  15. Conclusions Plasticity of the binding pocket of MDM2 allows the binding of ligands of widely varying shapes and sizes Modulation of binding pocket leads to varying thermodynamics origin of the stability Y100 acts as a gatekeeper Lid-dynamics is correlated with Y100 orientation K51, K70, K94, R97 have role to steer the ligand towards binding pocket

  16. Acknowledgement Chandra S. Verma David P. Lane Sebastian Maurer-Stroh BMAD Group BII, A*STAR INCOB organizers

  17. K70 K94 K51 R97 K70 K94 R97 Y100 K51 Y100

  18. H-bond !!

  19. p53 binding pocket *Uhrinova et al., JMB 2005

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