Introduction
The
human glucagon receptor (
GCGR) is one of 15 secretin-like, or Class B,
G-protein coupled receptors (GPCRs). Like other GPCRs, it has a helical domain and a globular N-terminus (ECD).
Function
The glucagon receptor plays an important role in glucose homeostasis. During times of fasting (or low blood sugar) the pancreas dispatches glucagon to activate the GCGR in the liver. The binding of glucagon stimulates gluconeogenesis, through adenylate cyclase that initiates protein kinase A (PKA) activity[1]. This pathway synthesizes glucose, elevating blood sugar levels.
Structure
Class B vs. Class A
In contrast to class A glucagon receptors which have a proline kink, in all secretin-like class B glucagon receptors there is a Glycine at position 393 in Helix VII which allows for a . This glycine helical bend is fully conserved in all secretin-like class B receptors and is an important part of the FQGxxVxxYCF motif.
Another important structural component found in all secretin-like class B receptors are the two conserved
salt bridges found between
Arg 346 and
Glu 406 and Arg 173 and Glu 406
. These salt bridges are a distinct feature of class B receptors only because their interaction results in the distinct stalk found only in class B receptors
[2].
As a part of the interface between helices VI, V, and III, a Class B-specific hydrogen bond occurs between Asn 318 of Helix V and Leu 242 of Helix III.
GCGR-Specific Traits
Helix I Stalk Region
The tip of Helix I extends above the cell membrane into the extracellular space creating a . This region is longer than any other class of GPCR and extends three α-helical turns above the plane of the membrane. It is proposed that the stalk helps to capture the glucagon peptide and facilitates it's insertion into the 7tm[2].
Intracellular Helix VIII
The GCGR also contains an intracellular Helix VIII that is comprised of roughly 20 amino acids at the C-terminal end. This helix tilts approximately 25 degrees away from the membrane - the corresponding position in class A receptors are turned toward the membrane[2]. Although researchers are not entirely sure of its function, this helix is completely conserved in class B structures.
Binding Pocket
The class B GPCR has the widest and longest binding pocket. The distance between the EC tips of Helicies II and VI as well as between the tips of Helicies III and VII are some of the largest among the GPCRs[2]. As a result, the binding cavity of GCGR is located deeper inside the molecule.
Other Unique Structural Features
An important interface stabilization interaction between Helices I and VII occurs between Ser 152 of Helix I and Ser 390 of Helix VII. Due to their close proximity to one another, they form an important which stabilizes the structure of GCGR.
Glucagon Binding
Research has shown that class B GCPRs exist in either an open or closed conformation differentiating between the receptor's active and inactive states. The active, or open conformation, is characterized by an intracellular outward movement of helicies V and VI (breaking hydrogen bonds between Arg173-Ser305 and Glu245-Thr351) citation needed and an extracellular rotation of the ECD until it is almost perpendicular to the membrane surface citation needed. While the stalk region of Helix I helps to facilitate the motion of the ECD, intracellular G-protein coupling and extracellular glucagon binding stabilized this active state. In the abscence of glucagon, however, the GCGR adopts a closed conformation in which all three of the extracellular loops of the 7tm (ECL1, ECL2, and ECL3) can interact with the ECD citation needed. In this closed state, the ECD covers the extracellular surface of the 7tm. To transition between states, the ECD rotates and moves down towards the 7tm domain. This transition mechanism is consistent with the "two-domain" binding mechanism of class B GCPRs in which (1) the C-terminus of the ligand first binds to the ECD allowing (2) the N-terminus of the ligand to interact with the 7tm and activate the protein citation needed.
Clinical Relevance
Because of GCGR's role in glucose homeostasis, GCGRis a potential drug target for Type 2 diabetes. Specifically, molecules that antagonize the glucagon receptor may be able to lower blood sugar levels. Amongstexperimental treatments, two antibodies, mAb1 and mAb23, target the ECD domain of the GCGR interrupting glucagon binding[3]. While the entire cleft of the ECD is blocked by mAb1, mAb3 blocks glucagon binding by stabilizing a conformation of the ECD that promotes receptor inactivation citation needed. Another antibody, mAb7, inhibits GCGR allosterically[4]. Through binding to a site outside of the binding pocket, mAb7 inhibits the receptor without interacting with essential glucagon binding residues. Disrupting the normal interactions between the ECD and the 7tm domains, these antibodies inhibit the receptor's function and help to lower blood glucose level.
