Structural and dynamic insights into ligand recognition and activation of somatostatin receptor 3

Somatostatin receptor 3 (SSTR3) exerts critical biological functions such as negatively regulating hormone release and cell proliferation, making it a promising therapeutic target for endocrine disorders and nonfunctioning pituitary tumors. However, the development of more effective and safer somatostatinergic therapies is limited due to a lack of molecular understanding of the ligand recognition and conformational dynamics of SSTR3. Here, we report the cryo-EM structure of the human SSTR3-Gi complex bound to octreotide at 2.90 Å resolution. Our structures reveal the molecular mechanisms of ligand recognition and receptor activation. Furthermore, mutagenesis analyses reveal that residue R203⁵·³⁵ of SSTR3 and F294⁷·³⁵ of SSTR2 play critical roles in mediating the subtype selectivity of octreotide. Using electron paramagnetic resonance spectroscopy, we have investigated the conformational dynamics of SSTR3. Our findings demonstrate that during ligand binding or G protein coupling, the labeled site on transmembrane helix 6 (TM6) of SSTR3 progressively becomes exposed to the extracellular environment and exhibits increased dynamical characteristics. Our work provides structural and dynamic insights that will facilitate the rational design of subtype-selective drugs targeting SSTRs and possessing improved therapeutic profiles.