title: The predicted ensemble of low-energy conformations of human somatostatin receptor subtype 5 and the binding of antagonists.
abstract: Human somatostatin receptor subtype 5 (hSSTR5) regulates cell proliferation and hormone secretion. However, the identification of effective therapeutic small-molecule ligands is impeded because experimental structures are not available for any SSTR subtypes. Here, we predict the ensemble of low-energy 3D structures of hSSTR5 using a modified GPCR Ensemble of Structures in Membrane BiLayer Environment (GEnSeMBLE) complete sampling computational method. We find that this conformational ensemble displays most interhelical interactions conserved in class A G protein-coupled receptors (GPCRs) plus seven additional interactions (e.g., Y2.43-D3.49, T3.38-S4.53, K5.64-Y3.51) likely conserved among SSTRs. We then predicted the binding sites for a series of five known antagonists, leading to predicted binding energies consistent with experimental results reported in the literature. Molecular dynamics (MD) simulation of 50 ns in explicit water and lipid retained the predicted ligand-bound structure and formed new interaction patterns (e.g. R3.50-T6.34) consistent with the inactive μ-opioid receptor X-ray structure. We suggest more than six mutations for experimental validation of our prediction. The final predicted receptor conformations and antagonist binding sites provide valuable insights for designing new small-molecule drugs targeting SSTRs.
authors.affiliation: Materials & Process Simulation Center (MC 139-74), California Institute of Technology, Pasadena, CA 91125 (USA).
authors.forename: Sijia S
authors.initials: SS
authors.lastname: Dong
authors.forename: Ravinder
authors.initials: R
authors.lastname: Abrol
authors.forename: William A
authors.initials: WA
authors.lastname: Goddard
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D017481:Receptors, Somatostatin; C094573:somatostatin receptor 5
keywords: G protein-coupled receptors (GPCRs); computational chemistry; docking; molecular dynamics; protein structures; somatostatin receptor subtype 5 (SSTR5)