TY - JOUR
T1 - Macrolide antibiotics allosterically predispose the ribosome for translation arrest
AU - Sothiselvam, Shanmugapriya
AU - Liu, Bo
AU - Han, Wei
AU - Ramu, Haripriya
AU - Klepacki, Dorota
AU - Atkinson, Gemma Catherine
AU - Brauer, Age
AU - Remm, Maido
AU - Tenson, Tanel
AU - Schulten, Klaus
AU - Vaźquez-Laslop, Nora
AU - Mankin, Alexander S.
N1 - This work was supported by National Institutes of Health Grants R01GM104370 (to A.S.M. and N.V.-L.) and 9P41GM104601 (to K.S.) and National Science Foundation Grant
PHY0822613 (to K.S.). MD modeling was facilitated by the Great Lakes Consortium grant for Petascale Computation. A.B. and M.R. were supported by Estonian Ministry of Education Grant SF0180026s09 and by the European Regional Development Fund. G.C.A. was supported by Estonian Science Foundation Grant ETF9020 and European Social Fund Grant “Mobilitas” MJD99.
PY - 2014/7/8
Y1 - 2014/7/8
N2 - Translation arrest directed by nascent peptides and small cofactors controls expression of important bacterial and eukaryotic genes, including antibiotic resistance genes, activated by binding of macrolide drugs to the ribosome. Previous studies suggested that specific interactions between the nascent peptide and the antibiotic in the ribosomal exit tunnel play a central role in triggering ribosome stalling. However, here we show that macrolides arrest translation of the truncated ErmDL regulatory peptide when the nascent chain is only three amino acids and therefore is too short to be juxtaposed with the antibiotic. Biochemical probing and molecular dynamics simulations of erythromycin-bound ribosomes showed that the antibiotic in the tunnel allosterically alters the properties of the catalytic center, thereby predisposing the ribosome for halting translation of specific sequences. Our findings offer a new view on the role of small cofactors in the mechanism of translation arrest and reveal an allosteric link between the tunnel and the catalytic center of the ribosome.
AB - Translation arrest directed by nascent peptides and small cofactors controls expression of important bacterial and eukaryotic genes, including antibiotic resistance genes, activated by binding of macrolide drugs to the ribosome. Previous studies suggested that specific interactions between the nascent peptide and the antibiotic in the ribosomal exit tunnel play a central role in triggering ribosome stalling. However, here we show that macrolides arrest translation of the truncated ErmDL regulatory peptide when the nascent chain is only three amino acids and therefore is too short to be juxtaposed with the antibiotic. Biochemical probing and molecular dynamics simulations of erythromycin-bound ribosomes showed that the antibiotic in the tunnel allosterically alters the properties of the catalytic center, thereby predisposing the ribosome for halting translation of specific sequences. Our findings offer a new view on the role of small cofactors in the mechanism of translation arrest and reveal an allosteric link between the tunnel and the catalytic center of the ribosome.
KW - Azithromycin
KW - Ketolides
KW - Solithromycin
UR - https://www.scopus.com/pages/publications/84904016052
U2 - 10.1073/pnas.1403586111
DO - 10.1073/pnas.1403586111
M3 - Journal article
C2 - 24961372
AN - SCOPUS:84904016052
SN - 0027-8424
VL - 111
SP - 9804
EP - 9809
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 27
ER -