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Sandbox Reserved 1165

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This Sandbox is Reserved from Jan 11 through August 12, 2016 for use in the course CH462 Central Metabolism taught by R. Jeremy Johnson at the Butler University, Indianapolis, USA. This reservation includes Sandbox Reserved 1160 through Sandbox Reserved 1184.

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Human Glucagon Class B G Protein-Coupled Receptors (GPCRs)

1 Introduction
2 Structure
3 Extracellular Tips
4 How These Structures Lead to Function

Introduction

, also known as secretin-like receptors, are a subfamily of the more well known class A (rhodopsin-like) glucagon receptor family. 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).

Image:Proteopedia Image 1.png

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. 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.

Image:Amino Acid Sequence.jpg

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Clinical Relevancy

Of the fifteen human class B GPCRs, eight have been identified as potential drug target. Therapeutic agents have been created from the peptides themselves within this protein, but overall pharmaceutical companies have had difficulty creating agents that act on family B GPCRS. There is an outward appearance and inherent flexibility in the class B GCGR 7TM because of conserved hydrogen bonds that flank a glycine residue, and this structure along with the ECD and its role of interactions on the extracellular side of receptors may provide evidence to how class B receptors adjust its conformational spectra for various receptors. Researchers hope to show how these conformations can be utilized in potential treatments of a wide array disorders.

References

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 </StructureSection>
+==Clinical Relevancy==
+Of the fifteen human class B GPCRs, eight have been identified as potential drug target. Therapeutic agents have been created from the peptides themselves within this protein, but overall pharmaceutical companies have had difficulty creating agents that act on family B GPCRS. There is an outward appearance and inherent flexibility in the class B GCGR 7TM because of conserved hydrogen bonds that flank a glycine residue, and this structure along with the ECD and its role of interactions on the extracellular side of receptors may provide evidence to how class B receptors adjust its conformational spectra for various receptors. Researchers hope to show how these conformations can be utilized in potential treatments of a wide array disorders.
 == References ==
 <references/>

Sandbox Reserved 1165

From Proteopedia

Revision as of 12:33, 22 March 2016

Human Glucagon Class B G Protein-Coupled Receptors (GPCRs)

Contents

Introduction

Structure

Extracellular Tips

How These Structures Lead to Function

Clinical Relevancy

References

Views

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