Understanding the common themes and diverse roles of the second extracellular loop (ECL2) of the GPCR super-family

- Extracellular loop 2 (ECL2) is a key GPCR domain.
- ECL2 is usually a β-hairpin but can form other structures.
- ECL2 can be directly involved with the ligand-receptor functions.
- ECL2 is also involved in as biased agonism and allosteric modulation.
- These properties of ECL2 make it an important site for rational drug design.

The extracellular loops (ECLs) of G protein-coupled receptors (GPCRs) can bind directly to docked orthosteric or allosteric ligands, they can contain transient contact points for ligand entry into the transmembrane (TM) bundle and they can regulate the activation of the receptor signalling pathways. Of the three ECLs, ECL2 is the largest and most structurally diverse reflecting its functional importance. This has been shown through biochemical techniques and has been supported by the many subsequent crystal structures of GPCRs bound to both agonists and antagonists. ECL2 shares common structural features between (and sometimes across) receptor sub-families and can facilitate ligand entry to the TM core or act directly as a surface of the ligand-binding pocket. Structural similarities seem to underpin common binding mechanisms; however, where these exist, variations in primary sequence ensure ligand-binding specificity. This review will compare current understanding of the structural themes and main functional roles of ECL2 in ligand binding, activation and regulation of the major families of GPCRs.