» Articles » PMID: 1092341

Some Characteristics of and Structural Requirements for the Interaction of 24,25-dihydrofusidic Acid with Ribosome - Elongation Factor G Complexes

Overview
Journal Biochemistry
Specialty Biochemistry
Date 1975 Apr 22
PMID 1092341
Citations 24
Authors
Affiliations
Soon will be listed here.
Abstract

Fusidic acid inhibits polypeptide chain elongation by binding to the ribosome - elongation factor-G - GDP complex and thereby preventing its dissociation. The experiments reported here quantitate the interaction of the antibiotic [3H]-24,25-dihydrofusidic acid, an active analog of fusidic acid, with the ribosome - elongation factor-G - GDP comples. All components of the complex are essential for [3H]-24,25-dihydrofusidic acid binding. The stoichiometry of the interaction is ca. 1:1, and the Ka apparent, as determined by equilibrium dialysis, is 2.6 times 10-6 M-minus 1. It is further shown that GTP and GDP are equally effective in forming complexes to which the antibiotic may bind, whereas GMP and beta,gamma-methyleneguanosine triphosphate will not form complexes to which the antibiotic may bind. In order to examine the structural basis of the mode of antibiotic action shown by fusidic acid, we have considered two activities of 21 structural analogs of this antibiotic: ability to bind to the aforementioned ternary complex and ability to stabilize this complex. The comparative binding capability of the analogs were extablished through competition experiments with [3H]-24,25-dihydrofusidic acid. The data obtained from these experiments can be summarized as follows. (1) The C17-20 double bond of fusidic acid appears to be critical for both binding and complex stabilization activities. (2) A carboxyl group in the vicinity of the C20 carbon is also essential for both activities. (3) Modifications of other functional groups in the molecule can lead to significantly decreased stabilization of the ternary ribosome complex and/or ability to compete with [3H]-24,25-dihydrofusidic acid for binding to the complex, but do not demonstrate absolute structural requirements for either activity.

Citing Articles

Crystal Structure of Elongation Factor G1.

Gao X, Yu X, Zhu K, Qin B, Wang W, Han P Front Mol Biosci. 2021; 8:667638.

PMID: 34540889 PMC: 8446442. DOI: 10.3389/fmolb.2021.667638.


Synthesis of Fusidic Acid Derivatives Yields a Potent Antibiotic with an Improved Resistance Profile.

Chavez M, Garcia A, Lee H, Lau G, Parker E, Komnick K ACS Infect Dis. 2021; 7(2):493-505.

PMID: 33522241 PMC: 8713577. DOI: 10.1021/acsinfecdis.0c00869.


Mechanism of fusidic acid inhibition of RRF- and EF-G-dependent splitting of the bacterial post-termination ribosome.

Borg A, Pavlov M, Ehrenberg M Nucleic Acids Res. 2016; 44(7):3264-75.

PMID: 27001509 PMC: 4838388. DOI: 10.1093/nar/gkw178.


Fusidic acid targets elongation factor G in several stages of translocation on the bacterial ribosome.

Borg A, Holm M, Shiroyama I, Hauryliuk V, Pavlov M, Sanyal S J Biol Chem. 2014; 290(6):3440-54.

PMID: 25451927 PMC: 4319013. DOI: 10.1074/jbc.M114.611608.


Mechanism of elongation factor-G-mediated fusidic acid resistance and fitness compensation in Staphylococcus aureus.

Koripella R, Chen Y, Peisker K, Koh C, Selmer M, Sanyal S J Biol Chem. 2012; 287(36):30257-67.

PMID: 22767604 PMC: 3436278. DOI: 10.1074/jbc.M112.378521.