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Biophys J, August 1998, p. 601-611, Vol. 75, No. 2

A Proposed Structure for Transmembrane Segment 7 of G Protein-Coupled Receptors Incorporating an Asn-Pro/Asp-Pro Motif

Karel Konvicka, Frank Guarnieri, Juan A. Ballesteros, and Harel Weinstein

Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, New York 10029, USA

Transmembrane segment (TMS) 7 has been shown to play an important role in the signal transduction function of G-protein-coupled receptors (GPCRs). Although transmembrane segments are most likely to adopt a helical structure, results from a variety of experimental studies involving TMS 7 are inconsistent with it being an ideal alpha -helix. Using results from a search of the structure database and extensive simulated annealing Monte Carlo runs with the new Conformational Memories method, we have identified the conserved (N/D)PxxY region of TMS 7 as the major determinant for deviation of TMS 7 from ideal helicity. The perturbation consists of an Asx turn and a flexible "hinge" region. The Conformational Memories procedure yielded a model structure of TMS 7 which, unlike an ideal alpha -helix, is capable of accommodating all of the experimentally derived geometrical criteria for the interactions of TMS 7 in the transmembrane bundle of GPCRs. In the context of the entire structure of a transmembrane bundle model for the 5HT2a receptor, the specific perturbation of TMS 7 by the NP sequence suggests a structural hypothesis for the pattern of amino acid conservation observed in TMS 1, 2, and 7 of GPCRs. The structure resulting from the incorporation of the (N/D)P motif satisfies fully the H-bonding capabilities of the 100% conserved polar residues in these TMSs, in agreement with results 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.

Biophys J, August 1998, p. 601-611, Vol. 75, No. 2
© 1998 by the Biophysical Society   0006-3495/98/08/601/11  $2.00


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