Activation Mechanism of T1R2/T1R3 by D-Glucose and L-Glucose
They appear to activate human T1R2/T1R3 through a ==shared sugar recognition mechanism that involves the venus flytrap 40;VFT 41; domains, with an especially strong piece of evidence for the T1R3 VFT residue S147==.[...
They appear to activate human T1R2/T1R3 through a ==shared sugar recognition mechanism that involves the venus flytrap 40;VFT 41; domains, with an especially strong piece of evidence for the T1R3 VFT residue S147==.[:cite[1]{ln=2}], [:cite[2]{ln=1}], [:cite[2]{ln=2}], [:cite[2]{ln=6}], [:cite[3]{ln=1}], [:cite[3]{ln=3}], [:cite[3]{ln=6}] The paper shows that ==both D glucose and L glucose activate the canonical T1R2/T1R3 receptor in a dose dependent way==.[:cite[4]{ln=1}] It also shows that ==both enantiomers can activate T1R2 only and T1R3 only transfections 40;interpreted by the authors as homodimers 41;==, which means each subunit can contribute to glucose sensing on its own.[:cite[5]{ln=2}], [:cite[4]{ln=2}], [:cite[4]{ln=3}], [:cite[4]{ln=4}], [:cite[4]{ln=5}], [:cite[6]{ln=4}] The strongest residue level evidence is for ==T1R3 S147==.[:cite[2]{ln=2}], [:cite[3]{ln=1}], [:cite[3]{ln=3}] The authors predicted computationally that ==S147 in the T1R3 VFT interacts with both D glucose and L glucose==, then tested that prediction experimentally.[:cite[2]{ln=6}], [:cite[3]{ln=6}] When they mutated ==S147 to alanine 40;S147A 41; in T1R3 alone, activation by both D glucose and L glucose was completely abolished==.[:cite[5]{ln=3}], [:cite[7]{ln=2}], [:cite[3]{ln=7}], [:cite[8]{ln=4}] That is the cleanest evidence in the paper that ==both enantiomers rely on a common T1R3 VFT contact point==.[:cite[2]{ln=6}], [:cite[7]{ln=2}], [:cite[3]{ln=6}], [:cite[3]{ln=7}] The rescue pattern matters too.[:cite[7]{ln=3}], [:cite[3]{ln=8}], [:cite[8]{ln=4}] When ==T1R3 S147A was coexpressed with T1R2, the response matched T1R2 only transfection rather than full wild type T1R2/T1R3 behavior==, which implies that the mutant T1R3 had lost its glucose driving contribution and the remaining signal was largely coming through T1R2.[:cite[5]{ln=3}], [:cite[7]{ln=3}], [:cite[3]{ln=8}], [:cite[8]{ln=4}] So the practical read is this: ==D glucose and L glucose use overlapping receptor machinery, not two completely separate mechanisms==.[:cite[5]{ln=3}], [:cite[2]{ln=6}], [:cite[3]{ln=7}] The evidence supports shared engagement of sugar binding regions in the VFT domains, especially T1R3 S147, and likely T1R2 VFT as well, since the paper notes that sugar binding in T1R2 VFT is already established and that both T1R2 and T1R3 VFT domains are known to bind neutral sugars such as glucose.[:cite[2]{ln=1}], [:cite[1]{ln=2}] That said, the paper also shows they are ==not functionally identical in how they drive signaling==.[:cite[4]{ln=6}], [:cite[10]{ln=1}], [:cite[9]{ln=1}], [:cite[9]{ln=2}], [:cite[9]{ln=3}] L glucose reaches an early plateau, whereas D glucose keeps increasing without saturation in the tested range, and this pattern remains even in partial transfections.[:cite[4]{ln=6}], [:cite[10]{ln=1}], [:cite[9]{ln=2}], [:cite[9]{ln=3}] So the best evidence based conclusion is: ==same general receptor activation route, but different signaling/dose response behavior once bound==.[:cite[11]{ln=2}], [:cite[9]{ln=2}], [:cite[9]{ln=3}], [:cite[9]{ln=6}] One more residue came up: ==T1R2 R317==.[:cite[5]{ln=5}], [:cite[12]{ln=1}], [:cite[12]{ln=2}], [:cite[13]{ln=4}] The paper found that the ==R317G substitution reduces sensitivity to L glucose==, lowering potency and efficacy.[:cite[12]{ln=2}], [:cite[12]{ln=3}], [:cite[5]{ln=5}] But the authors also say this position is ==outside the binding site== and that they did ==not determine its exact mechanism==; they suggest possible effects on trafficking, stability, or allosteric behavior instead.[:cite[13]{ln=6}], [:cite[13]{ln=7}] So ==R317 affects sensitivity, but S147 is the clearer direct mechanistic residue for glucose recognition in this study==.[:cite[3]{ln=6}], [:cite[3]{ln=7}], [:cite[13]{ln=6}], [:cite[13]{ln=7}] ==Bottom line: D glucose and L glucose both activate T1R2/T1R3 by engaging shared sugar sensing elements in the receptor, with strong evidence for a critical T1R3 VFT residue 40;S147 41;, but they produce distinct dose response profiles, so their activation is similar in route and different in signaling behavior.==[:cite[2]{ln=2}], [:cite[2]{ln=6}], [:cite[4]{ln=1}], [:cite[4]{ln=6}], [:cite[7]{ln=2}], [:cite[3]{ln=7}], [:cite[9]{ln=2}]