modulation of p53 binding to mdm2: computational studies reveal important roles of tyr100
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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Modulation of p53 binding to MDM2: computational studies
reveal important roles of Tyr100
Shubhra G Dastidar, David P Lane, Chandra S Verma
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p53 network
Vogelstein, B., Lane, D. P., and Levine, A. J. (2000). Surfing the p53 network. Nature 408: 307-310.
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Transactivation domain of p53: 17-29
MDM2: 25-109
Kussie et al., Science 1996
Vassilev et al., Science 2004
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• P27S mutation Δ ΔG = -2.3kcal/mol
W23
L26
F19
P27
E17TFSD LWKLL PEN29
Zondlo et al. Biochemistry 2006
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S27
S27 Δ ΔG = -4.2 kcal/mol
Δ Δ G = -4.7 kcal/mol
Crystallographically observed binding mode of WT is retained
Dastidar, S.G., Lane D.P., Verma C.S., J. Am. Chem. Soc. 2008
α-helix is propagated by another turn
Δ ΔH = -0.8-T Δ ΔS = -3.4 Δ ΔG = -4.2
Δ Δ H = -3.6-T Δ ΔS = -1.1 Δ Δ G = -4.7
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Y100 orients as in wild type Y100 flips in
Ligand with extended C-terminus Ligand with helical conformation
Dastidar, S.G., Lane D.P., Verma C.S., J. Am. Chem. Soc. 2008
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Modulation of binding site of MDM2 while binding to a variety of ligands in PDB
p53
12/1 peptideOptimized peptide
β-hairpin
Nutlin
Optimized peptide
IC50 ~ 10-2000nM
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L26
Y100
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Y100
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E28K70
E17
K51
R65
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K70
K51
R97
K94
Y100
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K94
R97
K51
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ApoAfter MD in presence of p53
p53 binding pocket
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N-terminal lid
p53 binding pocket
C-terminal end,connects other domains of MDM2
Y100
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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
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Acknowledgement
• Chandra S. Verma• David P. Lane• Sebastian Maurer-Stroh• BMAD Group• BII, A*STAR• INCOB organizers
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K70
K70
K51
K51
R97R97
K94
K94
Y100
Y100
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H-bond !!
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p53 binding pocket
*Uhrinova et al., JMB 2005