TI  - Structure of the  <prot>MDM2</prot>  oncoprotein bound to the  <prot>p53</prot>  tumor suppressor
      transactivation domain.
PG  - 948-53
AB  - The  <prot>MDM2</prot>  oncoprotein is a cellular inhibitor of the  <prot>p53</prot>  tumor suppressor
      in that it can bind the transactivation domain of <prot>p53</prot> and downregulate its
      ability to activate transcription. In certain cancers,  <prot>MDM2</prot>  amplification
      is a common event and contributes to the inactivation of  <prot>p53</prot> . The crystal
      structure of the 109-residue amino-terminal domain of  <prot>MDM2</prot>  bound to a
      15-residue transactivation domain peptide of  <prot>p53</prot>  revealed that  <prot>MDM2</prot>  has a
      deep hydrophobic cleft on which the  <prot>p53</prot>  peptide binds as an amphipathic
      alpha helix. The interface relies on the steric complementarity between
      the <prot>MDM2</prot> cleft and the hydrophobic face of the <prot>p53</prot> alpha helix and, in
      particular, on a triad of <prot>p53</prot> amino acids-Phe19, Trp23, and Leu26-which
      insert deep into the <prot>MDM2</prot> cleft. These same <prot>p53</prot> residues are also involved
      in transactivation, supporting the hypothesis that <prot>MDM2</prot> inactivates <prot>p53</prot> by
      concealing its transactivation domain. The structure also suggests that
      the amphipathic alpha helix may be a common structural motif in the
      binding of a diverse family of transactivation factors to the <prot>TATA-binding
      protein</prot>-associated factors.
AD  - Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering
