Molecular Insights into the Transmembrane Domain of the XXXX .

@entity268 @entity16544 @entity368 @entity5010 @entity1521
UNASSIGNED: The @entity5010 ( @entity5010 ) is a G protein-coupled receptor (GPCR) that is member of the @entity368 -rich repeat subfamily (LGR). In the absence of crystal structure, the success of rational design of ligands targeting the receptor internal cavity depends on the quality of the @entity5010 models built. In this subfamily, @entity16544 are characterized by the absence of @entity1521 compared to most receptors, raising the question of the structural conformation of these helices. To gain insight into the structural properties of these helices, we carried out bioinformatics and experimental studies. Evolutionary analysis of the LGR family revealed a deletion in @entity16544 but provided no information on TM2. Wild type residues at positions 2.58, 2.59 or 2.60 in TM2 and/or at position 5.50 in @entity16544 were substituted to @entity1521 . Depending on the position of the @entity1521 substitution, different effects were observed on membrane expression, glycosylation, constitutive @entity268 activity and responses to thyrotropin. Only @entity1521 substitution at position 2.59 maintained complex glycosylation and high membrane expression, supporting occurrence of a bulged TM2. The @entity5010 transmembrane domain was modeled by homology with the orexin 2 receptor, using a protocol that forced the deletion of one residue in the @entity16544 bulge of the template. The stability of the model was assessed by molecular dynamics simulations. @entity16544 straightened during the equilibration phase and was stable for the remainder of the simulations. Our data support a structural model of the @entity5010 transmembrane domain with a bulged TM2 and a straight @entity16544 that is specific of glycoprotein hormone receptors.
