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Background
The human glucagon receptor 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 which consists of two antiparallel β-sheets and an 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 GCPR in the liver. Glucagon binding with the Glucagon Receptor stimulates gluconeogenesis, which synthesizes glucose and elevates blood sugar levels.
Structure
Class B Structural Components
Helix I "Stalk" Region
The of Helix I is longer than any other class of GCPR 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 GCPR as the longest and deepest binding pocket. The distance between the EC tips of Helicies II and VI are the largest among the GCPRs and the distance
Unique components to the GPCR
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 .
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 this, it is being looked as a potential drug target for Type 2 diabetes. Molecules that antagoinze the glucagon receptor may be able to lower blood sugar levels.
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