We have used a comprehensive array of techniques to characterize the energy-transduction domain of the sarco/endoplasmic reticulum calcium transport ATPase (SERCA), including x-ray crystallography, solution biochemistry, fluorescence spectroscopy, molecular dynamics simulation, and small-molecule activation. The energy-transduction domain of SERCA mediates long-range allosteric coupling of ATP hydrolysis in the cytosolic headpiece to Ca2+ transport in the transmembrane domain. In heart failure, decreased SERCA activity correlates with disease progression in patients; increasing SERCA activity by drug or gene therapy reverses heart failure in animal models. Here we solved the x-ray crystal structure of SERCA in complex with a novel small-molecule activator, thus identifying a unique binding site on the energy-transduction domain. Conformation-specific proteolytic cleavage and intramolecular glutaraldehyde cross-linking was used to determine activator effect on SERCA headpiece structure. Fluorescence spectroscopy was used to identify kinetic transitions accelerated by the activator. We propose a structural and biochemical mechanism for small-molecule activation of SERCA. Interestingly, the activator site is located vicinal to the binding site of sarcolipin (SLN), a muscle phosphoprotein that regulates SERCA energy expenditure and muscle metabolism to provide resistance against diet-induced obesity and extreme cold through non-shivering thermogenesis. SLN uncoupling of ATP hydrolysis from Ca2+ transport by SERCA was examined using microsecond MD simulation, finding that the cytosolic domain of SLN induces a salt bridge-mediated structural rearrangement of the energy-transduction domain, which allosterically uncouples SERCA by disrupting Ca2+ occlusion at residue E309 in transport site II, and thereby facilitating futile Ca2+ backflux in muscle. Our results demonstrate that the energy-transduction domain is a key control element that provides a structural motif for activation of Ca2+ transport by cardiac SERCA2a in heart failure and for uncoupling ATP hydrolysis by muscle SERCA1a in obesity.