A Structure-Based Approach to Understanding Somatostatin Receptor-4 Agonism (sst4)

• Published in: Journal of chemical information and modeling 2012-01, Vol.52 (1), p.171-186
• Main Authors: Liu, Zhaomin, Crider, A. Michael, Ansbro, Daniel, Hayes, Christina, Kontoyianni, Maria
• Format: Article
• Language: English
• Subjects: 3-D graphics; Amino Acid Sequence; Binding Sites; Biochemistry; Biological and medical sciences; Biological Products - chemistry; Biological Products - pharmacology; Crystal structure; Crystallography, X-Ray; Fundamental and applied biological sciences. Psychology; Humans; Hydrophobic and Hydrophilic Interactions; Interactions. Associations; Intermolecular phenomena; Models, Molecular; Molecular biophysics; Molecular Sequence Data; Protein Binding; Receptors, Adrenergic, beta - chemistry; Receptors, Somatostatin - agonists; Receptors, Somatostatin - chemistry; Statins; Structural Homology, Protein; Structure-Activity Relationship
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci200375j

It has been reported that somatostatin receptor subtypes 4 and 5 would be high-impact templates for homology modeling if their 3D structures became available. We have generated a homology model of the somatostatin receptor subtype 4 (sst4), using the newest active state β2 adrenoreceptor crystal structure, and subsequently docked a variety of agonists into the model-built receptor to elucidate the binding modes of reported agonists. Using experimental restraints, we were able to explain observed activity profiles. We propose two binding modes that can consistently explain findings for high-affinity agonists and reason why certain structures display low affinities for the receptor.