Crystal structure of elongation factor 4 bound to a clockwise ratcheted ribosome

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Science  08 Aug 2014:
Vol. 345, Issue 6197, pp. 684-687
DOI: 10.1126/science.1253525

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Better blood thinner, without bleeding

Blood thinners prevent heart attacks and strokes by making it harder for blood to clot, but these drugs can put patients at risk of dangerous bleeding. Now Moeckle et al. describe an enzyme that can prevent clots without this perilous side effect. They engineered the enzyme apyrase to remove the pro-clotting molecule ADP from the blood quickly. In dogs and mice with heart attacks, apyrase stopped blood cells from aggregating, the first step in forming a clot. At the highest dose, the animals suffered less heart damage and did not bleed excessively. In comparison, clopidogrel, a blood thinner used currently in patients, protected the heart less well and did cause excessive bleeding.

Science, this issue p. 684


Elongation factor 4 (EF4/LepA) is a highly conserved guanosine triphosphatase translation factor. It was shown to promote back-translocation of tRNAs on posttranslocational ribosome complexes and to compete with elongation factor G for interaction with pretranslocational ribosomes, inhibiting the elongation phase of protein synthesis. Here, we report a crystal structure of EF4–guanosine diphosphate bound to the Thermus thermophilus ribosome with a P-site tRNA at 2.9 angstroms resolution. The C-terminal domain of EF4 reaches into the peptidyl transferase center and interacts with the acceptor stem of the peptidyl-tRNA in the P site. The ribosome is in an unusual state of ratcheting with the 30S subunit rotated clockwise relative to the 50S subunit, resulting in a remodeled decoding center. The structure is consistent with EF4 functioning either as a back-translocase or a ribosome sequester.

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