Sandbox Reserved 1170: Difference between revisions

Like most G-protein coupled receptors, hGPR40 contains <scene name='72/721542/Transmembrane_helices/2'>seven transmembrane helices</scene> (<scene name='72/721542/Top_view_transmembrane_helices/3'>top view of TM helices</scene>). To obtain a crystallized structure of the protein, four <scene name='72/721541/Stabilizing_mutations/3'>stabilizing mutations</scene> (<scene name='72/721541/L42a/2'>L42A</scene>, <scene name='72/721541/F88a/2'>F88A</scene>, <scene name='72/721541/G103a/2'>G103A</scene>, <scene name='72/721541/Y202f/2'>Y202F</scene>) were made to increase expression levels and thermal stability of the protein. These mutations did not significantly impact the enzyme's binding affinity with a known agonist, Tak-875. A <scene name='72/721541/Lysozyme_crimson/1'>T4 Lysozyme</scene> (shown in crimson) was also added to intracellular loop 3 to aid in the formation of crystals. The lysozyme also had little effect on TAK-875 binding.<ref name="Srivastava"/> For clarity, the lysozyme is removed in all further renderings of hGPR40.

[[Image:Tak-875.png |300 px|right|thumb|Figure 4. Structure of TAK-875]] One example of an hGPR40 agonist is <scene name='72/721542/Tak875/2'>Tak-875</scene>. The carboxylate moiety of the agonist enters through the it of the auxiliary loop, interrupts the charge network, and binds with Arg 183, Arg 258, Tyr 91, and Tyr 240.<ref name="Srivastava"/> TAK-875 has shown efficacy in increasing insulin secretion and lowering blood glucose in rodent models of type 2 diabetes.<ref name="Burant"/> This drug was studied in stage III clinical trials and was able to significantly reduce [http://www.diabetes.co.uk/what-is-hba1c.html HbA1c] and fasting plasma glucose levels in Japanese patients with type 2 diabetes that was not controlled by diet and exercise. However, clinical trials were stopped shortly after this study because TAK-875 was suspected of causing liver damage.<ref name="Kaku">PMID:25787200</ref>