Crystal structure of the oxazolidinone antibiotic linezolid bound to the 50S ribosomal subunit.

The oxazolidinone antibacterials target the 50S subunit of prokaryotic ribosomes. To gain insight into their mechanism of action, the crystal structure of the canonical oxazolidinone, linezolid, has been determined bound to the Haloarcula marismortui 50S subunit. Linezolid binds the 50S A-site, near the catalytic center, which suggests that inhibition involves competition with incoming A-site substrates. These results provide a structural basis for the discovery of improved oxazolidinones active against emerging drug-resistant clinical strains.

Prion and doppel proteins bind to granule cells of the cerebellum.

We reported that expression of the cellular prion protein (PrPC) rescues doppel (Dpl)-induced cerebellar degeneration in mice. To search for protein(s) that mediate this process, we fused the C-termini of mouse (Mo) PrP and Dpl to the Fc portion of an IgG. Although both MoPrP-Fc and MoDpl-Fc bound to many regions of the brain, we observed restricted binding to granule cells in the cerebellum, suggesting a scenario in which granule cells express a protein that mediates Dpl-induced neurodegeneration. Because granule cells do not express PrPC, it seems unlikely that MoPrP-Fc binding reflects a ligand that is involved in the conversion of PrPC into PrPSc, the disease-causing isoform. In contrast, the dominant-negative MoPrP(Q218K)-Fc not only binds to granule cells but also binds to neurons of the molecular layer where PrPC is expressed. These findings raise the possibility that the cells of the molecular layer express an auxiliary protein, provisionally designated protein X, which is involved in prion formation and is likely to be distinct from the protein that mediates Dpl-induced degeneration. Although the binding of the dominant-negative MoPrP(Q218K)-Fc to cells in the molecular layer expressing PrPC is consistent with a scenario for the binding of MoPrP(Q218K)-Fc to protein X, the absence of PrPSc deposition in the molecular layer requires that PrP(Sc), once formed there, be readily transported to the cerebellar white matter where PrPSc is found. Identifying the ligands to which PrP-Fc, Dpl-Fc, and dominant-negative PrP bind may provide new insights into the functions of PrPC and Dpl as well as the mechanism of PrPSc formation.