Somatostatin receptors (SSTRs) are a critical family of G protein-coupled receptors (GPCRs) that play a vital role in regulating hormone secretion and inhibiting tumor growth. Specifically, SSTR5, among its five subtypes, is highly expressed in the pituitary gland, governing the release of important hormones such as adrenocorticotropic hormone, prolactin, and growth hormone. This makes SSTR5 a promising target for the treatment of endocrine disorders and tumors associated with hormonal imbalances.

In a recent study published in PNAS, a research team led by Eric H. Xu and Zhao Lihua from the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences utilized single-particle cryo-electron microscopy techniques to uncover the three-dimensional structures of SSTR5 in complex with the natural neuropeptide agonist cortistatin-17 (CST17) and the clinically-approved drug octreotide. By meticulously determining cryo-EM structures of SSTR5 bound to CST17 and octreotide, researchers were able to observe that the binding of these agonists triggers a rearrangement of a “hydrophobic lock” within the receptor, leading to an outward movement of specific helices and facilitating G protein coupling and activation.

The unique findings of this study shed light on the precise mechanisms of SSTR5 activation by different ligands, providing insights into the structural and functional aspects of how the receptor recognizes and interacts with neuropeptide and drug agonists. This knowledge opens up avenues for developing novel and highly selective SSTR5 modulators with decreased off-target effects, offering promising therapeutic opportunities for an array of conditions including acromegaly, pituitary adenomas, neuroendocrine tumors, and hormonal imbalances.

Overall, the study’s contribution to understanding the intricate workings of SSTR5 and its interactions with specific agonists marks a significant advancement in the field of molecular pharmacology and holds promise for the development of targeted therapies for a wide range of endocrine-related disorders.

Chemistry

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