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case western reserve university

BIOCHEMISTRY
 
 

Dr. Menachem Shoham

Associate Professor

Pub Med:

Dr. Menachem Shoham

The focus is on the function and crystal structure of two classes of proteins: (1) Proteins that kill bacteria and could be developed into antibiotics (2) Seven transmembrane helix proteins and their interaction with G proteins and modulating proteins.

Colicin E3, a protein that kills bacteria by ribosome inactivation
Colicins kill E. coli by a process that involves binding to a surface receptor, entering the cell and finally intoxicating it. The lethal action of colicin E3 is a specific cleavage in the ribosomal decoding A-site. The crystal structure of colicin E3 in complex with its immunity protein (IP), reveals a Y-shaped molecule with the receptor-binding domain forming a 100 Å long stalk and the two globular heads of the translocation domain (T) and the catalytic domain (C) comprising the two arms. IP is buried between T and C. Rather than blocking the active site, IP prevents access of the active site to the ribosome. Cytotoxins such as colicin E3 have potential therapeutic value as novel antibiotics.
Surface representation. Colicin E3 is shown in white, the immunity protein in magenta and the active site of the RNase domain in cyan. (left) The binary colicin E3 - immunity protein complex. (right) Immunity protein is removed from the complex.
Surface representation of intact colicin E3 docked onto the 30S ribosomes from Thermus thermophilus. C, catalytic domain, T translocation domain, R receptor-binding domain, IP immunity protein. IP neither blocks the RNase active site of colicin E3 nor is there any steric hindrance with the substrate, the ribosome. The proposed mechanism of E3 inhibition by IP involves repulsion of the negatively charged molecules of IP and the ribosome. In this manner IP prevents E3 from approaching the ribosome.

 

Selected References

  • E. Ben-Zeev, R. Zarivach, M. Shoham, A. Yonath and M. Eisenstein. Prediction of the Structure of the Complex Between the 30S Ribosomal Subunit and Colicin E3 via Weighted-Geometric Docking. J. Biomol. Structure & Dynamics 20:669-676 (2003)

  • R. Zarivach, E. Ben-Zeev, N. Wu, T. Auerbach, A. Bashan, K. Jakes, K. Dickman, A. Kosmidis, F. Schluenzen, A. Yonath, M. Eisenstein and M. Shoham. On the Interaction of Colicin E3 with the Ribosome. Biochimie 84:447-454 (2002).

  • S. Soelaiman, K. Jakes, N. Wu, C. Li3, and M. Shoham. Crystal Structure of Colicin E3: Implications for Cell Entry and Ribosome Inactivation. Mol. Cell 8:1053-1062, 2001

  • Lin F, Immormino RM, Shoham M, Medof ME, Bulk production and functional analyses of mouse CD55's native and deglycosylated active domains., Arch Biochem Biophys 393: 1, 67-72, Sep1, 2001

  • Thibonnier M, Coles P, Thibonnier A, Shoham M, The basic and clinical pharmacology of nonpeptide vasopressin receptor antagonists., Annu Rev Pharmacol Toxicol 41:175-202, , 2001

  • M. Shoham. Rusticyanin. In Handbook of Metalloproteins. (Editors K. Wieghardt, R. Huber, T. Poulos & A. Messerschmidt) pp. 1235-1241 (2001).

  • Thibonnier M, Coles P, Conarty DM, Plesnicher CL, Shoham M, A molecular model of agonist and nonpeptide antagonist binding to the human V(1) vascular vasopressin receptor., J Pharmacol Exp Ther 294: 195-203, 2000.

  • C. Li, D. Zhao, A. Djebli, and M. Shoham. Crystal structure of colicin E3 immunity protein: an inhibitor to a ribosome-inactivating RNase. Structure with Folding & Design 7:1365-1372, 1999.