Crystal structure of the ectodomain of Methuselah, a Drosophila G protein-coupled receptor associated with extended lifespan

The Drosophila mutant methuselah (mth) was identified from a screen for sin gle gene mutations that extended average lifespan. Mth mutants have a 35% i ncrease in average lifespan and increased resistance to several forms of st ress, including heat, starvation, and oxidative damage. The protein affecte d by this mutation is related to G protein-coupled receptors of the secreti n receptor family. Mth, like secretin receptor family members, has a large N-terminal ectodomain, which may constitute the ligand binding site. Here w e report the 2.3-Angstrom resolution crystal structure of the Mth extracell ular region, revealing a folding topology in which three primarily p-struct ure-containing domains meet to form a shallow interdomain groove containing a solvent-exposed tryptophan that may represent a ligand binding site. The Mth structure is analyzed in relation to predicted Mth homologs and potent ial ligand binding features.