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

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.

Prospect of acromegaly therapy: molecular mechanism of clinical drugs octreotide and paltusotine

“…2e–i ). The binding of SSTR2 with octreotide exhibits the same recognition mechanism compared with previous reporting 21 , 22 (Supplementary Fig. 4b, c ).…”

“…Identification of selective ligands toward specific subtypes is challenging, especially for developing orally active small-molecule ligand. The selective mechanisms of octreotide and the small molecule L-054,264 for activating group 2 SSTRs over group 1 members have been reported 22 , 24 . The structure of SSTR2 in complex with paltusotine enabled the opportunity to examine ligand selectivity for distinguishing group 2 SSTRs, as paltusotine exerts higher selectivity and efficacy towards SSTR2 relative to other group 2 SSTRs (Fig.…”

Molecular simulations of SSTR2 dynamics and interaction with ligands

“…SST14 has a short half-life (< 3 min) and lacks selectivity towards the five SSTR isoforms. Differently, octreotide and lanreotide show higher affinity towards SSTR2 and a longer half-life (2 and 1 h, respectively) 10,15,16 . The non-peptide/ peptidomimetic analogues of SST14 have shown increased half-life and potency towards specific SSTR isoforms as well 17 .…”

“…Robertson and co-workers released the first cryo-EM structures of SSTR2 bound with SST14 and octreotide 24 . New structures soon followed, also in complex with other ligands 14,15,25,26 and one in the apo inactive form 27 (Table S1). An important feature of the SSTR2…”

Interaction of Radiopharmaceuticals with Somatostatin Receptor 2 Revealed by Molecular Dynamics Simulations

“…In the last year, different structures of SSTR2 in multiple conformational states have been published. ,,,,, Noteworthy, most of these structures are in complex with agonist ligands, which is often somatostatin or its analogous, like the octa-peptide octreotide. Both experimental and computational studies explored the conformational features of SSTR2 that are common to those of other class A GPCRs, and the key elements characterizing the binding with different types of ligands (see Figure S1 for an overview of the three-dimensional structure of SSTR2 and its main domains) .…”