Molecular Modeling of Transmembrane Helices 6 and 7 of the Heptahelical Lutropin Receptor

In response to ligand binding and activating mutations, the lutropin receptor undergoes a conformational change to trigger a cellular response. D556 is the most common locus for naturally occurring activating mutations of the lutropin receptor, and a D556A mutant is shown to be constitutively active. A water-mediated proton transfer is postulated as part of the transmembrane signaling mechanism. Using energy minimization and ab initio calculations, a hydrogen bonding network involving a highly constrained water molecule(s) and D556 (helix 6) and N593 / N597 / Y601 (helix 7) is presented.