Trp/Met/Phe hot spots in protein-protein interactions: potential targets in drug design

Curr Top Med Chem. 2007;7(10):999-1005. doi: 10.2174/156802607780906717.


Protein-protein interactions are crucial to biological functions. Consequently, designing drugs to control protein-protein interactions is receiving increasing attention. Protein structures can associate in different ways. Analysis of the structures of protein-protein complexes using amino acid sequence order-independent multiple structural comparison algorithms, led us to conclude that the amino acids Trp, Met, and Phe are important for protein-protein interactions. Hence, in principle, drug design targeting the Trp/Met/Phe should modulate protein functions effectively. Several clusters of the Trp/Met/Phe residues are involved in the p53 protein-protein interactions. The best example in this regard is the Phe19/Trp23 of p53, which binds to transcriptional factors and to the MDM2 protein. In the HIV related proteins, the Trp/Met/Phe residues have roles in the dimerization of the transcriptase (p51/p66) and in cell-fusion processes, including the gp120-CD4 interaction and the gp41 six-helix bundle formation. Trp/Met/Phe residues are preferred in 'normal' functional protein-protein interactions and they also appear to be exploited in amyloid formation, especially the phenylalanine. Comparison of binding propensity and amyloid formation preference reveals that apart from Lysine, Isoleucine is the least structurally conserved in protein binding sites and has a high propensity in sequences forming amyloids. Thus, this may suggest that nature tends to avoid Ile conservation in protein-protein interaction to avoid amyloid formation. In this regards, Trp/Met/Phe as well as Ile may be targeted to modulate protein-protein interaction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Amyloid / chemistry
  • Animals
  • Binding Sites
  • Drug Design*
  • Gene Products, env / chemistry
  • Humans
  • Methionine / chemistry*
  • Models, Molecular
  • Molecular Sequence Data
  • Phenylalanine / chemistry*
  • Protein Binding
  • Protein Interaction Mapping
  • Sequence Alignment
  • Tryptophan / chemistry*
  • Tumor Suppressor Protein p53 / chemistry


  • Amyloid
  • Gene Products, env
  • Tumor Suppressor Protein p53
  • Phenylalanine
  • Tryptophan
  • Methionine