Chapter 4 - Ions as GPCR allosteric modulators

Abstract

Sodium ion (Na+) serves as a negative allosteric modulator (NAM) of class-A G protein-coupled receptors (GPCRs). In the middle of the transmembrane helix bundle of most class-A GPCRs, the conserved residues D2.50 and S3.39 bind Na+ to form a “Na+-centered water cluster.” The Na+ binding lowers the affinities of the GPCRs for their agonists and the efficacies of G proteins. The bound Na+ stabilizes the GPCR structure in the inactive state, and thereby prevents the transition to the active state. The crystal structure of leukotriene B4 receptor (BLT1) with its inverse agonist BIIL260 revealed that the positively charged benzamidine moiety of the bound BIIL260 occupies the site for the Na+-centered water cluster, and mimics its NAM mechanism. This chapter will review the NAM mechanism of Na+ in structural aspects including crystallographic studies and MD simulations, and introduce the mimicking mechanism of BIIL260 to stabilize the inactive state of BLT1 as the inverse agonist.