Naslov
Free and bound state structures of 6-O-methyl homoerythromycins and epitope mapping of their interactions with ribosomes

Autori
Novak, Predrag ; Barber, Jill ; Čikoš, Ana ; Arsić, Biljana ; Plavec, Janez ; Lazarevski, Gorjana ; Tepeš, Predrag ; Košutić-Hulita, Nada

Izvornik
Bioorganic and Medicinal Chemistry (0968-0896) 17 (2009), 16; 5857-5867

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
homoerythromycins ; free and ribosome-bound structures ; binding epitopes ; NMR and molecular modeling

Sažetak
The solution and solid state conformations of several 6-O-methyl homoerythromycins 1-4 were studied using a combination of X-ray crystallography, NMR spectroscopy and molecular modelling calculations. In the solid state 1 was found to exist as the two independent molecules with similar structures termed 3-endo-folded-out. In solution a significant conformational flexibility was noticed especially in the C2 to C5 region. The compounds 1 and 2 unlike 14-membered macrolides adopted the 3-endo-folded-out conformation while 3 and 4 existed in the classical folded-out conformation. TrNOESY and STD experiments showed that 1 and 2 bound to the E. coli ribosome while 3 and 4, lacking the cladinose sugar, did not exhibit binding activities, this being in accordance with biochemical data. The bound conformations were found to be similar to the free ones, some small differences were observed and discussed. The STD experiments provided evidence on binding epitopes. The structural parts of 1 and 2 in close contact with ribosome were similar, however the degree of saturation transfer was higher for 2. The differences between tr-nOe data and STD enhancements in 1 and 2 arouse as a consequence of structural changes upon binding and a closer proximity of 2 to the ribosome surface. An understanding of the molecular mechanisms involved in the interaction of macrolides with ribosomes can help in developing strategies aiming at design of potential inhibitors.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

POVEZANOST RADA