Sandbox Reserved 1170
From Proteopedia
| Line 1: | Line 1: | ||
==Human GPR40 == | ==Human GPR40 == | ||
| - | + | ||
This is a default text for your page '''Jacob Applegarth/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs. | This is a default text for your page '''Jacob Applegarth/Sandbox 1'''. 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 <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue. | ||
== Function == | == Function == | ||
| Line 12: | Line 11: | ||
The importance of these residues for agonist binding was determined by mutagenesis studies. Each of these residues have either a charged or polar R-group that allows them to develop a charge network. This network keeps the residues in a stable, unbound state until exposed to a substrate. When the substrate (an agonist) enters the binding pocket, four of the seven <scene name='72/721541/Hydrogen_binding_1/3'>Key Binding Residues</scene> interact directly with the carboxylate moiety of the agonist. In 2007 and 2009 researchers showed the presence of Arg 183 and Arg 258 in the binding pocket <ref name="Sum">PMID: 17699519</ref><ref name="Sum, C.">PMID:19068482</ref> Along with the two Arginine residues, the charge network incorporates two Tyrosine residues.These residues (Tyr 91 and Tyr 240) also stabilize the carboxylate of the agonists. It was further determined that Tyr 240 is epecially important for binding. Mutation of Tyr 240 caused a reduction in the binding affinity of TAK-875 by eight fold and had a significant effect on the Kd of the protein.<ref name="Srivastava"/> | The importance of these residues for agonist binding was determined by mutagenesis studies. Each of these residues have either a charged or polar R-group that allows them to develop a charge network. This network keeps the residues in a stable, unbound state until exposed to a substrate. When the substrate (an agonist) enters the binding pocket, four of the seven <scene name='72/721541/Hydrogen_binding_1/3'>Key Binding Residues</scene> interact directly with the carboxylate moiety of the agonist. In 2007 and 2009 researchers showed the presence of Arg 183 and Arg 258 in the binding pocket <ref name="Sum">PMID: 17699519</ref><ref name="Sum, C.">PMID:19068482</ref> Along with the two Arginine residues, the charge network incorporates two Tyrosine residues.These residues (Tyr 91 and Tyr 240) also stabilize the carboxylate of the agonists. It was further determined that Tyr 240 is epecially important for binding. Mutation of Tyr 240 caused a reduction in the binding affinity of TAK-875 by eight fold and had a significant effect on the Kd of the protein.<ref name="Srivastava"/> | ||
| - | === | + | === ECL2 === |
<scene name='72/721541/Ecl2/2'>ECl2 Loops</scene> | <scene name='72/721541/Ecl2/2'>ECl2 Loops</scene> | ||
| - | Although it may be different in many | + | Although it may be different in many ways, hGPR40 is similar to most G protein coupled receptors because it contains a highly conserved hairpin loop. This extracellular loop (ECL2), is accompanied by a disulfide bond and serves an important role in the protein. In hGPR40, ECL2 has two sections: a beta sheet and an auxiliary loop. The [[beta sheet]] (shown in cyan) spans helices 4 and 5. hGPR40's ECL2 differs from that of other proteins because it contains an auxiliary loop (magenta) of 13 extra residues. The entire extracellular loop has low mobility and flexibility. The allows it to act as a cap for the binding pocket. The only exception to the low flexibility is the tip of the auxiliary loop, which corresponds to residues Asp 152-Asn 155. This area of greater mobility allows for substrates to enter the binding site.<ref name="Srivastava"/> |
| - | + | ||
== Clinical Relevance == | == Clinical Relevance == | ||
| + | By signaling predominantly through Gaq/11, GPR40 increases intracellular calcium and activates phospholipases to generate diacylglycerols resulting in increased insulin secretion. Synthetic small-molecule agonists of GPR40 enhance insulin secretion in a glucosedependent manner in vitro and in vivo with a mechanism similar to that found with fatty acids. GPR40 agonists have shown efficacy in increasing insulin secretion and lowering blood glucose in rodent models of type 2 diabetes.<ref name="Burant">PMID:23882043</ref> | ||
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes. | This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes. | ||
Revision as of 23:35, 28 March 2016
Contents |
Human GPR40
This is a default text for your page Jacob Applegarth/Sandbox 1. Click above on edit this page to modify. Be careful with the < and > signs.
Function
Human GPR40 (hGPR40) is a G-protein coupled receptor that binds free fatty acids to enhance glucose dependent insulin signaling.[1]
Structure
Like most G-protein coupled receptors, hGPR40 contains seven transmembrane helices. In order obtain a crystallized structure of the protein, four (, , , ) were made to increase expression levels and thermal stability of the protein.[1]
Charge Network
hGPR40 has a distinct binding pocket that is established by seven key residues.The importance of these residues for agonist binding was determined by mutagenesis studies. Each of these residues have either a charged or polar R-group that allows them to develop a charge network. This network keeps the residues in a stable, unbound state until exposed to a substrate. When the substrate (an agonist) enters the binding pocket, four of the seven interact directly with the carboxylate moiety of the agonist. In 2007 and 2009 researchers showed the presence of Arg 183 and Arg 258 in the binding pocket [2][3] Along with the two Arginine residues, the charge network incorporates two Tyrosine residues.These residues (Tyr 91 and Tyr 240) also stabilize the carboxylate of the agonists. It was further determined that Tyr 240 is epecially important for binding. Mutation of Tyr 240 caused a reduction in the binding affinity of TAK-875 by eight fold and had a significant effect on the Kd of the protein.[1]
ECL2
Although it may be different in many ways, hGPR40 is similar to most G protein coupled receptors because it contains a highly conserved hairpin loop. This extracellular loop (ECL2), is accompanied by a disulfide bond and serves an important role in the protein. In hGPR40, ECL2 has two sections: a beta sheet and an auxiliary loop. The beta sheet (shown in cyan) spans helices 4 and 5. hGPR40's ECL2 differs from that of other proteins because it contains an auxiliary loop (magenta) of 13 extra residues. The entire extracellular loop has low mobility and flexibility. The allows it to act as a cap for the binding pocket. The only exception to the low flexibility is the tip of the auxiliary loop, which corresponds to residues Asp 152-Asn 155. This area of greater mobility allows for substrates to enter the binding site.[1]
Clinical Relevance
By signaling predominantly through Gaq/11, GPR40 increases intracellular calcium and activates phospholipases to generate diacylglycerols resulting in increased insulin secretion. Synthetic small-molecule agonists of GPR40 enhance insulin secretion in a glucosedependent manner in vitro and in vivo with a mechanism similar to that found with fatty acids. GPR40 agonists have shown efficacy in increasing insulin secretion and lowering blood glucose in rodent models of type 2 diabetes.[4]
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.
</StructureSection>
References
- ↑ 1.0 1.1 1.2 1.3 Srivastava A, Yano J, Hirozane Y, Kefala G, Gruswitz F, Snell G, Lane W, Ivetac A, Aertgeerts K, Nguyen J, Jennings A, Okada K. High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. Nature. 2014 Jul 20. doi: 10.1038/nature13494. PMID:25043059 doi:http://dx.doi.org/10.1038/nature13494
- ↑ Sum CS, Tikhonova IG, Neumann S, Engel S, Raaka BM, Costanzi S, Gershengorn MC. Identification of residues important for agonist recognition and activation in GPR40. J Biol Chem. 2007 Oct 5;282(40):29248-55. Epub 2007 Aug 15. PMID:17699519 doi:http://dx.doi.org/10.1074/jbc.M705077200
- ↑ Sum CS, Tikhonova IG, Costanzi S, Gershengorn MC. Two arginine-glutamate ionic locks near the extracellular surface of FFAR1 gate receptor activation. J Biol Chem. 2009 Feb 6;284(6):3529-36. doi: 10.1074/jbc.M806987200. Epub 2008, Dec 8. PMID:19068482 doi:http://dx.doi.org/10.1074/jbc.M806987200
- ↑ Burant CF. Activation of GPR40 as a therapeutic target for the treatment of type 2 diabetes. Diabetes Care. 2013 Aug;36 Suppl 2:S175-9. doi: 10.2337/dcS13-2037. PMID:23882043 doi:http://dx.doi.org/10.2337/dcS13-2037
