Ubiquitin structural biology

Proteasome inhibitors have been instrumental in identifying numerous protein substrates and in elucidating the importance of the proteasome/ubiquitin pathway in many biological processes. Initially, non-specific cell-penetrating peptide aldehydes were used for this purpose. More recently, it became possible to synthesize compounds with increased potency and selectivity (Adams et al. 1998 Elofsson et al. 1999). Furthermore, based on the crystal structure of the yeast and bovine liver CP (Groll et al. 1997 Unno et al. 2002), molecular modeling can now be used to engineer improved inhibitors. 

The biologic function of Ras is mediated by its ability to activate downstream cytoplasmic signaling networks through binding to a panel of effector proteins. The Ras-effector interaction is mediated through interactions between the core effector domain (amino acids 32 0) of Ras (see Fig. 2) and the specific residues within the Ras-binding domain (RBD) or Ras-association domain (RA) found in most Ras effector proteins. The RBDs and RA domains of effector proteins do not exhibit primary sequence homology, but instead they share a common tertiary structure that consists of an ubiquitin superfold, which forms critical contacts with Ras (33). 

Alexeev, D., Barlow, P. N., Bury, S. M., et al. (2003) Synthesis, structural and biological studies of ubiquitin mutants containing (2S, 4S)-5-fluoroleucine residues strategically placed in the hydrophobic core. ChemBioChem, 4(9), 894—896. 

Love SG, Muir TW, Ramage R, Shaw KT, Alexeev D, Sawyer L, Kelly SM, Price NC, Arnolds JE, Me MP, and Mayer ly. Synthetic, Structural and Biological Studies of the Ubiquitin System Synthesis and Crystal Structure on an Analogue Containing Unnatural Amino Acids. Biochem J 1997 323 727-734. 

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