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. Author manuscript; available in PMC: 2020 Apr 1.
Published in final edited form as: Trends Pharmacol Sci. 2019 Mar 11;40(4):278–293. doi: 10.1016/j.tips.2019.02.003

Figure 2: Three proposed models of aGPCR activation.

Figure 2:

(A) In the first model, NTF and N-terminal GAIN domains conceal the conserved, cryptic tethered agonist Stachel structure in the CTF. Binding of extracellular ligand, possibly combined with mechanical force, removes the NTF, thereby exposing the Stachel structure, which interacts with extracellular loops of the 7TM domain and initiates conformational changes leading to constitutive downstream G protein signaling. (B) In the second model, ligand binding induces conformational changes independent of Stachel structure exposure, leading to transient and reversible downstream G protein signaling. (C) In the third model, ligand binding induced conformational changes that result in exposure of the Stachel structure and Stachel-dependent, potentially transient downstream signaling mediated through the 7TM.