Receptor antagonists targeting transmembrane domains

Abstract

Polytopic membrane proteins contain alpha-helical transmembrane (TM) domains which interact in a highly specific manner during assembly of the molecules. Destruction of this interaction is suggested as a method of specific regulation of protein function. G-protein coupled receptors (GPCR) represent a superfamily of proteins that mediate the function of neurotransmitters and peptide hormones and are involved in viral entry and perception of light, smell and taste. GPCRs are characterised by the presence of seven TM domains. Structural analogues of TM domains of GPCR are demonstrated to be potent receptor antagonists. Targeting the specific interactions between TM domains of GPCRs represents a general approach for the design of antagonists for any GPCR with a known primary structure. Structure-activity studies conducted on chemokine receptors define the structural requirement for a potent and selective antagonist. A TM targeting approach can also be applied to multimembrane spanning proteins of other classes since specific interactions between TM domains are vitally important for the functions of a diverse set of surface proteins.

• chemokine receptors
• GPCR
• membrane proteins
• receptor antagonist
• transmembrane domains