This cover image shows the ryanodine receptor Ca2+ channel (RyR) cryo-EM map with docked X-ray crystal structures of the ABC domains of RyR and a regulatory protein, FKBP. Also shown are the average locations of FRET donor probes on FKBP, as determined from simulations, and the identified location of a fluorescent biosensor peptide bound within RyR2, as determined by trilateration using FRET distances. For more detail see the article of Svensson et al. in this week’s issue of Biophysical Journal.

3D graphics and visualization are important tools that we use to better understand the function, structure, and dynamics of the proteins that we study. The 3D molecular graphics in the cover figure were displayed using Visual Molecular Dynamics (VMD) and the scene was then rendered using the TACHYON ray-tracing software, which is included with VMD (http://www.ks.uiuc.edu/Research/vmd/). Final editing, merging multiple layers and highlights, were done in Adobe Photoshop.

This research focuses on the ryanodine receptor, which mediates the release of Ca2+ from the sarcoplasmic reticulum that triggers cardiac and skeletal muscle contraction. We also study the Ca2+-ATPase (SERCA) that pumps Ca2+ from the cytosol into the sarcoplasmic reticulum lumen and thus relaxes the muscle. The common theme is the use of site-specific spectroscopic probes to measure atomic-scale distances that, in combination with molecular modeling and simulations guided by structural data, provide insights into the function and dynamics of these important membrane proteins. We will use this understanding to aid in the development of therapeutic discovery tools for muscle disease and heart failure.

We have developed a multi-scale approach that includes data from cryo-EM and X-ray crystallography in combination with molecular simulations of fluorescent probes and a set of FRET distance measurements. We believe that our approach will be effective for mapping sites of interest in many large protein complexes.

This work was the result of a collaborative effort involving three research teams. For more information about the scientists involved, and their current research visit our websites:

http://www.ucdmc.ucdavis.edu/pharmacology/faculty/bers/

http://researchfaculty.brighamandwomens.org/BRIProfile.aspx?id=5937

http://ddt.umn.edu/

- Bengt Svensson, Tetsuro Oda, Florentin R. Nitu, Yi Yang, Iustin Cornea, Ye Chen-Izu, James D. Fessenden, Donald M. Bers, David D. Thomas, and Razvan L. Cornea