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Structural insights into the activation of somatostatin receptor 2 by cyclic SST analogues.

<div class='caption-title'>The cryo-EM structure of SSTR2–DNGi complex.</div>
<div class='caption-title'>Interactions between SST β-turn residues and SSTR2 transmembrane residues.</div>
<div class='caption-title'>Conformational change analysis of SSTR2 receptor upon binding of lanreotide.</div>
Bo Q, Yang F, Li Y, Meng X, Zhang H, Zhou Y, Ling S, Sun D, Lv P, Liu L, Shi P, Tian C
OpenAccess logo Cell Discov 8 47 (2022)
Related entries: 7xat, 7xau

Cited: 17 times
EuropePMC logo PMID: 35595746

Abstract

The endogenous cyclic tetradecapeptide SST14 was reported to stimulate all five somatostatin receptors (SSTR1-5) for hormone release, neurotransmission, cell growth arrest and cancer suppression. Two SST14-derived short cyclic SST analogues (lanreotide or octreotide) with improved stability and longer lifetime were developed as drugs to preferentially activate SSTR2 and treat acromegalia and neuroendocrine tumors. Here, cryo-EM structures of the human SSTR2-Gi complex bound with SST14, octreotide or lanreotide were determined at resolutions of 2.85 Å, 2.97 Å, and 2.87 Å, respectively. Structural and functional analysis revealed that interactions between β-turn residues in SST analogues and transmembrane SSTR2 residues in the ligand-binding pocket are crucial for receptor binding and functional stimulation of the two SST14-derived cyclic octapeptides. Additionally, Q1022.63, N2766.55, and F2947.35 could be responsible for the selectivity of lanreotide or octreotide for SSTR2 over SSTR1 or SSTR4. These results provide valuable insights into further rational development of SST analogue drugs targeting SSTR2.

Articles - 7xav mentioned but not cited (2)

  1. Molecular simulations of SSTR2 dynamics and interaction with ligands. Gervasoni S, Guccione C, Fanti V, Bosin A, Cappellini G, Golosio B, Ruggerone P, Malloci G. Sci Rep 13 4768 (2023)
  2. Identification of a Novel SSTR3 Full Agonist for the Treatment of Nonfunctioning Pituitary Adenomas. Modena D, Moras ML, Sandrone G, Stevenazzi A, Vergani B, Dasgupta P, Kliever A, Gulde S, Marangelo A, Schillmaier M, Luque RM, Bäuerle S, Pellegata NS, Schulz S, Steinkühler C. Cancers (Basel) 15 3453 (2023)


Reviews citing this publication (3)

  1. Cortisol as a Target for Treating Mental Disorders: A Promising Avenue for Therapy. Patel VK, Vaishnaw A, Shirbhate E, Kore R, Singh V, Veerasamy R, Rajak H. Mini Rev Med Chem 24 588-600 (2024)
  2. The Role of Receptor-Ligand Interaction in Somatostatin Signaling Pathways: Implications for Neuroendocrine Tumors. Milewska-Kranc A, Ćwikła JB, Kolasinska-Ćwikła A. Cancers (Basel) 16 116 (2023)
  3. Pancreatic δ Cells: An Overlooked Cell in Focus. Golson ML. Adv Anat Embryol Cell Biol 239 141-155 (2024)

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