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Introduction

, also known as secretin-like receptors, are a subfamily of the more well known class A (rhodopsin-like) glucagon receptor family^[1] . Located in the liver, class B glucagon receptors (GCGRs) are activated by the binding of the hormonal peptide glucagon which leads to the release of glucose into the bloodstream and plays an essential role in glucose homeostasis. Class B GCGRs are composed of a seven transmembrane domain (7TM) and extracellular domain (ECD) that are of vital importance in glucagon binding. In comparison, class A vs. class B glucagon receptors share less than fifteen percent sequence homology, but both share this 7TM which is a primary area of comparison between the two.

Structure

Secretin-like receptors are composed entirely of alpha helices in their 7TM and ECD. A distinct feature of class B receptors is the N-terminal end of helix one in the 7TM. It extends an extra three helical turns into the ECD, and is longer than any of the class A receptors. This region, referred to as the "stalk" of class B receptors, is highly involved in glucagon binding and also helps in defining the orientation of the ECD with respect to the 7TM domain.

Extracellular Tips

The locations of the extracellular tips for class B glucagon receptors allow for a much wider and deeper binding cavity in the ligand-binding pocket, which is much more immense than any of the class A GCGRs. These wide ranges specifically occur between alpha helices two and six (green) and three and seven (red).

How These Structures Lead to Function

Structurally, the N-terminal extracellular domain (ECD) and the 7TM comprise the signature seven helical structure that is involved in signaling via coupling to heterotrimeric proteins that activate adenylate cyclase to increase the levels of intracellular cyclic AMP, and also heterotrimeric G proteins that increase inositol phosphate and intracellular calcium levels. The wider and deeper ligand-binding pocket of class B GPCRs allows for a vast array of receptors to be bound that allow for numerous functions activated by peptide receptors ^[2] . The conformation and orientation of the 7TM and the ECD regions dictate the functionality of the protein.There is an open and closed conformation of the GCGR. When glucagon binds to GCGR, the open conformation of GCGR is stabilized. There is no clear binding site location of the hormone peptide ligand. They do know the N-terminus of glucagon binds deep into the binding pocket.The amino acids at the N-terminus have the ability to form hydrogen bonds and ionic interactions.

Many of the residues that are in direct contact with the glucagon molecule are charged or are polar. There are also any bulk resides on glucagon that support the bulky resides on the GCGR. These residues are located within the binding pocket of the 7TM. There are specific amino acid interactions that hold the helices of the 7TM in the conformation that maximizes affinity, this includes a disulfide bond between Cys 294 and Cys 224 that serves to hold the ECL1 and ECL2 in the proper orientation. Also, the salt bridges between Glu 406, Arg 173, and Arg 346 that hold the conformation of affinity. Alpha helical structure of the stalk is imperative to the affinity and binding of the glucagon.