7T11

CryoEM structure of somatostatin receptor 2 in complex with Octreotide and Gi3.

Summary for 7T11

• Entry DOI: 10.2210/pdb7t11/pdb
• EMDB information: 25587
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-3, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: gpcr, receptor, complex, membrane protein, membrane protein-signaling protein complex, membrane protein/signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 160707.77

Authors

Robertson, M.J.,Skinotis, G. (deposition date: 2021-11-30, release date: 2022-03-09, Last modification date: 2022-03-30)

Primary citation

Robertson, M.J.,Meyerowitz, J.G.,Panova, O.,Borrelli, K.,Skiniotis, G.
Plasticity in ligand recognition at somatostatin receptors.
Nat.Struct.Mol.Biol., 29:210-217, 2022

PubMed Abstract: Somatostatin is a signaling peptide that plays a pivotal role in physiologic processes relating to metabolism and growth through its actions at somatostatin receptors (SSTRs). Members of the SSTR subfamily, particularly SSTR2, are key drug targets for neuroendocrine neoplasms, with synthetic peptide agonists currently in clinical use. Here, we show the cryogenic-electron microscopy structures of active-state SSTR2 in complex with heterotrimeric G and either the endogenous ligand SST14 or the FDA-approved drug octreotide. Complemented by biochemical assays and molecular dynamics simulations, these structures reveal key details of ligand recognition and receptor activation at SSTRs. We find that SSTR ligand recognition is highly diverse, as demonstrated by ligand-induced conformational changes in ECL2 and substantial sequence divergence across subtypes in extracellular regions. Despite this complexity, we rationalize several known sources of SSTR subtype selectivity and identify an additional interaction for specific binding. These results provide valuable insights for structure-based drug discovery at SSTRs.

PubMed: 35210615
DOI: 10.1038/s41594-022-00727-5

Experimental method

ELECTRON MICROSCOPY (2.7 Å)