Calcium homeostasis is central to excitation-contraction coupling in muscle. In this talk, I will focus on the structural analysis of a membrane protein complex between the sarcoplasmic reticulum Ca2+-ATPase (SERCA) and phospholamban (PLN), which is responsible for approximately 70% of the Ca2+ reuptake into the sarcoplasmic reticulum membrane, thereby controlling the relaxation phase of muscle. Using a combination of NMR methods, we mapped the conformational transitions of PLN free and bound to SERCA. I will illustrate how PLN conformational dynamics (i.e molecular motions) play a key role in the regulatory cycle of SERCA. Finally, I will demonstrate that by tuning the flexibility of PLN, it is possible to modulate the activity of SERCA. The latter represents a possible avenue for protein therapy designed to ameliorate muscle diseases and cardiomyopathy.