Phospholamban (PLN) is a type II membrane protein that inhibits the sarcoplasmic 
reticulum Ca(2+)-ATPase (SERCA), thereby regulating calcium homeostasis in 
cardiac muscle. In membranes, PLN forms pentamers that have been proposed to 
function either as a storage for active monomers or as ion channels. Here, we 
report the T-state structure of pentameric PLN solved by a hybrid solution and 
solid-state NMR method. In lipid bilayers, PLN adopts a pinwheel topology with a 
narrow hydrophobic pore, which excludes ion transport. In the T state, the 
cytoplasmic amphipathic helices (domains Ia) are absorbed into the lipid bilayer 
with the transmembrane domains arranged in a left-handed coiled-coil 
configuration, crossing the bilayer with a tilt angle of approximately 11° with 
respect to the membrane normal. The tilt angle difference between the monomer 
and pentamer is approximately 13°, showing that intramembrane helix-helix 
association forces dominate over the hydrophobic mismatch, driving the overall 
topology of the transmembrane assembly. Our data reveal that both topology and 
function of PLN are shaped by the interactions with lipids, which fine-tune the 
regulation of SERCA.