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Stabilization of G protein-coupled receptors by point mutations.

Type of publication Peer-reviewed
Publikationsform Review article (peer-reviewed)
Publication date 2015
Author Heydenreich Franziska M, Vuckovic Ziva, Matkovic Milos, Veprintsev Dmitry B,
Project NMR studies of GPCRs: Structure, dynamics and interactions with ligands and signaling proteins
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Review article (peer-reviewed)

Journal Frontiers in pharmacology
Volume (Issue) 6
Page(s) 82 - 82
Title of proceedings Frontiers in pharmacology
DOI 10.3389/fphar.2015.00082

Abstract

G protein-coupled receptors (GPCRs) are flexible integral membrane proteins involved in transmembrane signaling. Their involvement in many physiological processes makes them interesting targets for drug development. Determination of the structure of these receptors will help to design more specific drugs, however, their structural characterization has so far been hampered by the low expression and their inherent instability in detergents which made protein engineering indispensable for structural and biophysical characterization. Several approaches to stabilize the receptors in a particular conformation have led to breakthroughs in GPCR structure determination. These include truncations of the flexible regions, stabilization by antibodies and nanobodies, fusion partners, high affinity and covalently bound ligands as well as conformational stabilization by mutagenesis. In this review we focus on stabilization of GPCRs by insertion of point mutations, which lead to increased conformational and thermal stability as well as improved expression levels. We summarize existing mutagenesis strategies with different coverage of GPCR sequence space and depth of information, design and transferability of mutations and the molecular basis for stabilization. We also discuss whether mutations alter the structure and pharmacological properties of GPCRs.
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