Examples Of Plasticity

3.1. Amine Receptors:

From Ligand Recognition to Activation Mechanism

Conserved Ser and Thr residues can play different roles in maintaining the structure or regulating the activity of GPCRs. We hypothesize that these functional roles are related to the capability of these residues to affect the geometry of TMHs. To illustrate this point, this section discusses the example of amine receptors.

Fig. 5. Presence and degree of conservation of Pro residues in TMH3 of class A GPCRs. Only a few and very specific subfamilies feature this residue-for example, some peptide receptors at 3.29 (4% of class A), gonadotropin-releasing hormone and prostanoid receptors in 3.39 (1% of class A), or tachykinin receptors at 3.32 (1% of class A).

Fig. 5. Presence and degree of conservation of Pro residues in TMH3 of class A GPCRs. Only a few and very specific subfamilies feature this residue-for example, some peptide receptors at 3.29 (4% of class A), gonadotropin-releasing hormone and prostanoid receptors in 3.39 (1% of class A), or tachykinin receptors at 3.32 (1% of class A).

Sequence analysis of the amine receptor family reveals several conserved Ser or Thr residues in TMH3 (18), the helix with the fewest conserved Pro residues in the rhodopsin-like family of GPCRs (25) (Fig. 5). Whereas 3.37 and 3.39 positions are highly conserved in the entire amine receptor family (forming the Thr3.37-(Ala/Ser)3.38-Ser3.39 signature of amine receptors) and 3.30 and 3.47 are also conserved (to a lesser extent), other positions are conserved only within certain subfamilies (Fig. 6). Located in the center of the helical bundle, TMH3 interacts with nearly all the other helices, and, therefore, these polar residues could facilitate specific interhelical contacts. Our structural studies suggest an alternative role for these residues: Whereas the lack of Pro in this helix suggests that it will not feature strong hinges, these Ser and Thr can provide a certain degree of flexibility and plasticity to the helix, leading to various alternative TMH3 conformations that might represent different functional states of the receptor, as has been proposed for the D2 dopamine receptor (18). The actual distortions depend on the precise positions of Ser and Thr residues in TMH3. Because this helix is known to

Amine receptors

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