Accurate Determination of Conformational Transitions in Oligomeric Membrane Proteins

The structural dynamics governing collective motions in oligomeric membrane proteins play key roles in vital biomolecular processes at cellular membranes. In this study, we present a structural refinement approach that combines solid-state NMR experiments and molecular simulations to accurately describe concerted conformational transitions identifying the overall structural, dynamical, and topological states of oligomeric membrane proteins. The accuracy of the structural ensembles generated with this method is shown to reach the statistical error limit, and is further demonstrated by correctly reproducing orthogonal NMR data. We demonstrate the accuracy of this approach by characterising the pentameric state of phospholamban, a key player in the regulation of calcium uptake in the sarcoplasmic reticulum, and by probing its dynamical activation upon phosphorylation. Our results underline the importance of using an ensemble approach to characterise the conformational transitions that are often responsible for the biological function of oligomeric membrane protein states

Trials in "true" dyslipidemic patients are urged to reconsider comprehensive lipid management as a means to reduce residual cardiovascular risk

Randomized cardiovascular trials aimed to reduce the excessive residual risk in high-risk patients through a more aggressive LDL-cholesterol control or targeting triglycerides or HDL-cholesterol levels have shown a null or, at best, limited incremental benefit. In some cases, the treatment produced meaningful effects only in study subgroups. As a consequence, some compounds were withdrawn (e.g. nicotinic acid derivatives and CETP inhibitors), whereas others (fibrates) are utilized with reluctance due to the low level of evidence-based data. By reviewing these trials analytically, we identified a common feature that might explain their meagre results: most of them involved patients generically at high cardiovascular risk with normal or near normal lipid levels and not patients with "true" dyslipidemia, who would receive the treatment if it were part of usual care. These observations may warrant reexamining a central criterion of pragmatism, eligibility, in the outline of forthcoming cardiovascular trials with novel lipid-modifying drugs