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spinqualitylabelsall models Human Glucagon Class B GPCR ( 7tm PDB: 4l6r, ECD PDB: 4ers) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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Contents 1 Background 2 Function 3 Structure 3.1 Class B vs. Class A 3.2 GCGR-Specific Traits 3.2.1 Helix I "Stalk" Region 3.2.2 Intracellular Helix VIII 3.2.3 Binding Pocket 3.2.4 Other Unique Structural Features 4 Glucagon Binding 5 Clinical Relevance

Background

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 (shown in blue) and a globular N-terminus (shown in magenta). As its name suggests, the 7tm is made up of alpha helices that pass through the membrane seven times. The extracellular domain has a α-β-β structure consisting of two antiparallel β-sheets and a N-terminal α-helix^[3].

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^[4]. This pathway synthesizes glucose, elevating blood sugar levels.

Structure

Class B vs. Class A

As opposed 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 and therefore this 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 .

Since there is no conservation of these residues in class A receptors these salt bridges are likely an important feature of secretin-like class B receptors.

The 7tm region has a conserved disulfide bond at which helps to stabilize the 7tm fold. This bond is conserved among both Class A and Class B receptors.The ECD region of Class B GCPRs is defined by three conserved disulfide bonds. These bonds occur at , , and .

As a part of the interface stabilization between helices VI, V, and III, a class B specific hydrogen bond occurs between N 318 of Helix V and L 242 of Helix III.

GCGR-Specific Traits

Helix I "Stalk" Region

The of Helix I is longer than any other class of GPCR and extends 3 α-helical turns above the plane of the membrane. It helps to capture the glucagon peptide and facilitates it's insertion into the 7tm.

Intracellular Helix VIII

Binding Pocket

The Class B GPCR has the longest and deepest binding pocket. The distance between the EC tips of Helicies II and VI as well as between the tips between Helicies III and VII are some of the largest among the GPCRs.

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 serves to stabilize the structure of GCGR.

Glucagon Binding

Research has shown that Class B GCPRs exist in either an open or closed conformation. Transitioning between states, the ECD rotates and moves down towards the 7tm domain. The stalk region of Helix I helps to facilitate this motion of the ECD.

In its open state, the ECD and the stalk region of Helix 1 are almost perpendicular to the membrane surface. In the case of the human glucagon receptor, this open confirmation is stabilized by glucagon binding. In the absence of glucagon, however, the GCPR adopts a closed conformation in which all three of the extracellular loops of the 7tm (ECL1, ECL2, and ECL3) can interact with the ECD. In this closed state, the ECD covers the extracellular surface of the 7tm.

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.​

Clinical Relevance

Because of GCGRs role in glucose homeostasis, it is a potential drug target for Type 2 diabetes. Specifically, molecules that antagoinze the glucagon receptor may be able to lower blood sugar levels.