A PROPOSED STRUCTURE FOR TRANSMEMBRANE SEGMENT-7 OF G-PROTEIN-COUPLEDRECEPTORS INCORPORATING AN ASN-PRO ASP-PRO MOTIF/

Transmembrane segment (TMS) 7 has been shown to play an important role in the signal transduction function of G-protein-coupled receptors (G PCRs). Although transmembrane segments are most likely to adopt a heli cal structure, results from a variety of experimental studies involvin g TMS 7 are inconsistent with it being an ideal alpha-helix. Using res ults from a search of the structure database and extensive simulated a nnealing Monte Carlo runs with the new Conformational Memories method, we have identified the conserved (N/D)PxxY region of TMS 7 as the maj or determinant for deviation of TMS 7 from ideal helicity. The perturb ation consists of an Asx turn and a flexible ''hinge'' region. The Con formational Memories procedure yielded a model structure of TMS 7 whic h, unlike an ideal alpha-helix, is capable of accommodating all of the experimentally derived geometrical criteria for the interactions of T MS 7 in the transmembrane bundle of GPCRs. In the context of the entir e structure of a transmembrane bundle model for the 5HT(2a) receptor, the specific perturbation of TMS 7 by the NP sequence suggests a struc tural hypothesis for the pattern of amino acid conservation observed i n TMS 1, 2, and 7 of GPCRs. The structure resulting from the incorpora tion of the (N/D)P motif satisfies fully the H-bonding capabilities of the 100% conserved polar residues in these TMSs, in agreement with re sults from mutagenesis experiments. The flexibility introduced by the specific structural perturbation produced by the (NP/DP) motif in TMS 7 is proposed to have a significant role in receptor activation.