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Function

Human GPR40 (hGPR40) is a G-protein coupled receptor that binds free fatty acids to enhance glucose dependent insulin signaling.^[3]

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.^[3]

Charge Network

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 ^[4][5] 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.^[3]

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.^[3]

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.^[6]

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