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The Predicted Ensemble of Low-Energy Conformations of Human Somatostatin Receptor Subtype 5 and the Binding of Antagonists

Dong, Sijia S. and Abrol, Ravinder and Goddard, William A., III (2015) The Predicted Ensemble of Low-Energy Conformations of Human Somatostatin Receptor Subtype 5 and the Binding of Antagonists. ChemMedChem, 10 (4). pp. 650-661. ISSN 1860-7179.

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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.

Item Type:Article
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URLURL TypeDescription Information
Dong, Sijia S.0000-0002-5811-9333
Abrol, Ravinder0000-0001-7333-6793
Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Received: January 20, 2015. Article first published online: 13 MAR 2015. The authors thank Adam R. Griffith for providing the docking program GenDock and Vaclav Cvicek for providing the Monte Carlo loop-building program. Support from donors to the Materials and Process Simulation Center (MSC), California Institute of Technology (USA) is acknowledged.
Subject Keywords:computational chemistry; docking; Gprotein-coupled receptors (GPCRs); molecular dynamics; protein structures; somatostatin receptor subtype5 (SSTR5)
Issue or Number:4
Record Number:CaltechAUTHORS:20150323-093730177
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Official Citation:Dong, S. S., Abrol, R. and Goddard, W. A. (2015), The Predicted Ensemble of Low-Energy Conformations of Human Somatostatin Receptor Subtype 5 and the Binding of Antagonists. ChemMedChem, 10: 650–661. doi: 10.1002/cmdc.201500023
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:55963
Deposited By: Tony Diaz
Deposited On:23 Mar 2015 18:00
Last Modified:09 Mar 2020 13:18

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