Book of Abstracts: Albany 2007

category image Albany 2007
Conversation 15
June 19-23 2007

The Roles of RNA in the Peptidyl Transferase Reaction and its Inhibition by Antibiotics

The structural basis of peptide bond formation and its inhibition has been illuminated from the high resolution crystal structures of the large ribosomal subunit from Haloarcula marismortui (Hma) complexed with substrates and intermediate analogues as well as structures of both the wild-type and mutant Hma subunit complexed with antibiotics. Upon binding of an aminoacylated-CCA to the A site, the rRNA of the ribosome?s peptidyl transferase center undergoes an ?induced fit? conformational change that reorients the ester linked peptidyl-CCA to expose and reposition the ester appropriately for nucleophilic to attack by the A-site alpha-amino group (1). In the absence of the A-site substrate the ester is protected from premature hydrolysis by ribosomal bases. The attacking alpha-amino group interacts with the 2'OH of A76 of the P-site substrate which presumably acts as a ?proton shuttle? from the alpha-amino group to the A76 3'OH (2). The oxyanion of the tetrahedral intermediate interacts with a ribosomal RNA positioned water molecule, and no metal ions are directly involved in catalysis. The structures of some two dozen antibiotics bound to the peptidyl transferase center show that each of these compounds is bound to one of several nearby, non-identical binding sites formed by rRNA. Complexes with mutant Hma subunits explain the structural basis of some antibiotic resistant mutants (3). This research is supported by grants from the NIH and The Agouron Institute.

References and Footnotes
  1. Schmeing, T.M. Huang, K.S., Kitchen, D.E., Strobel, S.A., Steitz, T.A. Nature 438, 520 (2005).
  2. Schmeing, T.M., Huang, K.S., Strobel, S.A., Steitz, T.A. Molec. Cell 20, 437 (2005).
  3. Tu, D. Blaha, G., Moore, P.B., Steitz, T.A. Cel1 121, 257 (2005).

Thomas A. Steitz

Department of Molecular Biophysics and Biochemistry Howard Hughes Medical Institute, Yale University 266 Whitney Avenue New Haven, CT 06520-8114