Membrane Proteins: Challenging Biotherapeutic Targets

Membrane proteins are about 30% of the human proteome and serve important physiological roles, including chemical transport, cell signaling, and energy transduction. Consequently, they represent about half of all drug targets. Small molecule drugs have been most commonly used to target membrane proteins, particularly G-protein coupled receptors and ion channels. However, these small molecules can lack selectivity and produce side effects. Biotherapeutics offer the potential to target specific conformations of proteins, thereby improving potency and selectivity. However, membrane proteins present significant challenges for biotherapeutic development, especially from their instability, insolubility, and limited expression levels. In this chapter, we explore biotherapeutic targeting of different families of membrane proteins, strategies to solubilize and stabilize membrane proteins for analysis, and mass spectrometry approaches to study their structure and interactions. Our focus will be primarily on biotherapeutic applications, but we will draw on promising emerging technologies that have been used in structural biology.