The protein ricin extracted from castor seeds has been shown to be an effective anti-tumor agent. It has a sugar binding subunit which allows a high affinity for transformed cells and a toxic subunit which stops proteins synthesis by enzymatically disrupting the ribosomal binding site for elongation factors. We have obtained excellent crystals of this toxin and have found at least one, and probably three, isomorphous heavy metal derivatives. We propose to solve the three dimensional structure of the protein x-ray diffraction and to eludicate its mechanism of action by a number of stratagems. We propose to compare its structure with the similar toxin PAP already under structural investigation in this laboratory. We also propose to carry out a complementary biochemical program to define key catalytic residues and to screen for competitive inhibitors. We anticipate that the structure and mechanism which should be elucidated by this study will further our knowledge of protein synthesis and may suggest a rationale basis for the design of anti-tumor agents.
NIH ExPorter
NIH ExPorter