Sandbox Reserved 1167

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Revision as of 17:50, 29 March 2016

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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This is a default text for your page '. Click above on edit this page' to modify. Be careful with the < and > signs. You may include any references to papers as in: the use of JSmol in Proteopedia ^[1] or to the article describing Jmol ^[2] to the rescue.

1 Background
2 Function
3 Structure
- 3.1 Class B Structural Components
- 3.2 Unique components to the GPCR
4 Glucagon Binding
5 Clinical Relevance

Background

Image:7tm labeled with membrane.png

The 7tm spans the cell's membrane

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 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 GCGR in the liver. The binding of glucagon with its receptor stimulates gluconeogenesis, through adenyllate cyclase that initiates protein kinase A (PKA) activity^[4]. This pathway synthesizes glucose, elevating blood sugar levels.

Structure

Class B Structural Components

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.

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.

This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

References

↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
↑ Yang L, Yang D, de Graaf C, Moeller A, West GM, Dharmarajan V, Wang C, Siu FY, Song G, Reedtz-Runge S, Pascal BD, Wu B, Potter CS, Zhou H, Griffin PR, Carragher B, Yang H, Wang MW, Stevens RC, Jiang H. Conformational states of the full-length glucagon receptor. Nat Commun. 2015 Jul 31;6:7859. doi: 10.1038/ncomms8859. PMID:26227798 doi:http://dx.doi.org/10.1038/ncomms8859
↑ PMID:PMC4321206

Retrieved from "http://52.214.119.220/wiki/index.php/Sandbox_Reserved_1167"

@@ Line 7: / Line 7: @@
 == Background ==
-[[Image:7tm_labeled_with_membrane.png|200 px|left|thumb|The 7tm spans the cell's membrane]]The human glucagon receptor is one of 15 secretin-like, or Class B, G-protein-coupled receptors (GPCRs). Like other GPCRs, it has a <scene name='72/721538/7tm_labeled_helicies/3'>7 trans-membrane </scene> helical domain (shown in blue) and a globular N-terminus <scene name='72/721538/Ecd/2'>extracellular domain</scene> (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<ref>PMID:26227798</ref>.
+[[Image:7tm_labeled_with_membrane.png|200 px|left|thumb|The 7tm spans the cell's membrane]]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 <scene name='72/721538/7tm_labeled_helicies/3'>7 trans-membrane </scene> helical domain (shown in blue) and a globular N-terminus <scene name='72/721538/Ecd/2'>extracellular domain</scene> (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<ref>PMID:26227798</ref>.
@@ Line 13: / Line 13: @@
 == 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. The [http://www.nature.com/nature/journal/v499/n7459/fig_tab/nature12393_F5.html binding of glucagon] with the Glucagon Receptor stimulates gluconeogenesis, which synthesizes glucose and elevates blood sugar levels.
+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 [http://www.nature.com/nature/journal/v499/n7459/fig_tab/nature12393_F5.html binding of glucagon] with its receptor stimulates gluconeogenesis, through adenyllate cyclase that initiates protein kinase A (PKA) activity<ref>PMID:PMC4321206</ref>. This pathway synthesizes glucose, elevating blood sugar levels.
@@ Line 27: / Line 27: @@
 ==== Binding Pocket ====
-The Class B GPCR as the longest and deepest binding pocket. The distance between the EC tips of Helicies II and VI are the largest among the GPCRs and the distance
+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.
 === Unique components to the GPCR ===