Sandbox Reserved 1170: Difference between revisions

[[Image:hydrogen bonding black.png|200 px|right|thumb|Figure 3. TAK-875 with key binding residues Tyr91, Arg183, Tyr240, and Arg258. These residues all hydrogen bond to the carboxylate moiety of TAK-875.]]hGPR40 has a distinct binding pocket that is established by <scene name='72/721541/All_binding_residues/3'>eight key residues</scene>: Tyr91, Glu172, Arg183, Ser187, Tyr240, Asn241, Asn244, and Arg258. The importance of these residues for agonist binding was determined by alanine [https://www.neb.com/applications/cloning-and-synthetic-biology/site-directed-mutagenesis mutagenesis] studies. Each of these residues have either a [http://www.proteinstructures.com/Structure/Structure/amino-acids.html charged or polar R-group] that creates a charge network that keeps these residues in a stable, unbound state until exposed to a substrate. When the substrate (an agonist) enters the binding pocket, four of the eight <scene name='72/721541/Hydrogen_binding_1/8'>key binding residues</scene> interact directly with the carboxylate moiety of the agonist by hydrogen bonding to it. These residues include two key arginines in the binding pocket, Arg183 and Arg258,<ref name="Sum">PMID: 17699519</ref><ref name="Sum, C.">PMID:19068482</ref> and two key tyrosine residues, Tyr91 and Tyr240 (Figure 3). Tyr240 is especially important for binding, as mutation of Tyr240 caused an eight fold reduction in the binding affinity of TAK-875 and had a significant effect on the [https://en.wikipedia.org/wiki/Dissociation_constant K_D] of the protein.<ref name="Srivastava"/>