 |
PDBsum entry 2npf
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Sordarin derivatives induce a novel conformation of the yeast ribosome translocation factor eef2.
|
|
|
Authors
|
|
R.Søe,
R.T.Mosley,
M.Justice,
J.Nielsen-Kahn,
M.Shastry,
A.R.Merrill,
G.R.Andersen.
|
|
|
Ref.
|
|
J Biol Chem, 2007,
282,
657-666.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The sordarins are fungal specific inhibitors of the translation factor eEF2,
which catalyzes the translocation of tRNA and mRNA after peptide bond formation.
We have determined the crystal structures of eEF2 in complex with two novel
sordarin derivatives. In both structures, the three domains of eEF2 that form
the ligand-binding pocket are oriented in a different manner relative to the
rest of eEF2 compared with our previous structure of eEF2 in complex with the
parent natural product sordarin. Yeast eEF2 is also shown to bind adenylic
nucleotides, which can be displaced by sordarin, suggesting that ADP or ATP also
bind to the three C-terminal domains of eEF2. Fusidic acid is a universal
inhibitor of translation that targets EF-G or eEF2 and is widely used as an
antibiotic against Gram-positive bacteria. Based on mutations conferring
resistance to fusidic acid, cryo-EM reconstructions, and x-ray structures of
eEF2, EF-G, and an EF-G homolog, we suggest that the conformation of EF-G
stalled on the 70 S ribosome by fusidic acid is similar to that of eEF2 trapped
on the 80 S ribosome by sordarin.
|
|
|
|
|
|
|
|
Figure 1.
FIGURE 1. The chemical structures of the natural products
sordarin and moriniafungin, as well as the semisynthetic analog
compound 1.
|
|
Figure 6.
FIGURE 6. A conserved conformation of eEF2 and EF-G. A,
fusidic acid related mutations mapped on the crystal structure
of EF-G (Protein Data Bank entry 1FNM). The backbone of 30
fusidic acid resistance residues (41) is colored blue. B,
mapping onto an EF-G model derived from the conformation of eEF2
observed by cryo-EM (see text for details). The closer approach
of domain III to domain I in this model is illustrated by the
distances between Leu^457 and Gln^117 (dashed lines). The
distance is 16.5 Å in the crystal structure and 12.1
Å in the modeled structure. C, overlay of domains III
(blue), IV (red), and V (green) of eEF2-sordarin and the
equivalent domains of the T. thermophilus EF-G homolog (all
domains gray) from Protein Data Bank entry 1WDT illustrating a
highly conserved domain arrangement.
|
|
|
|
|
|
The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2007,
282,
657-666)
copyright 2007.
|
|
|
|
|
|
|
