Interactions of designer antibiotics and the bacterial ribosomal aminoacyl-tRNA site.
The X-ray crystal structures for the complexes of three designer antibiotics, compounds 1, 2, and 3, bound to two models for the ribosomal aminoacyl-tRNA site (A site) at 2.5-3.0 Angstroms resolution and that of neamine at 2.8 Angstroms resolution are described. Furthermore, the complex of antibiotic 1 bound to the A site in the entire 30S ribosomal subunit of Thermus thermophilus is reported at 3.8 Angstroms resolution. Molecular dynamics simulations revealed that the designer compounds provide additional stability to bases A1492 and A1493 in their extrahelical forms. Snapshots from the simulations were used for free energy calculations, which revealed that van der Waals and hydrophobic effects were the driving forces behind the binding of designer antibiotic 3 when compared to the parental neamine.
Vernalis (R&D), Ltd., Granta Park, Cambridge, UK. j.murray@vernalis.com
James B
JB
Murray
Samy O
SO
Meroueh
Rupert J M
RJ
Russell
Georg
G
Lentzen
Jalal
J
Haddad
Shahriar
S
Mobashery
D000900:Anti-Bacterial Agents / Q000737:chemistry*; D018360:Crystallography, X-Ray; D009690:Nucleic Acid Conformation; D012329:RNA, Bacterial / Q000235:genetics*; D012346:RNA, Transfer, Amino Acyl / Q000737:chemistry*; D016963:Thermus thermophilus / Q000235:genetics*
D000900:Anti-Bacterial Agents; D012329:RNA, Bacterial; D012346:RNA, Transfer, Amino Acyl