Positive/Negative Allosteric Modulation Switching in an Umami Taste Receptor (T1R1/T1R3) by a Natural Flavor Compound, Methional.
Positive/Negative Allosteric Modulation Switching in an Umami Taste Receptor (T1R1/T1R3) by a Natural Flavor Compound, Methional.
复制标题
DOI：
10.1038/s41598-018-30315-x
复制
发表时间：
2018-08-07
影响因子：
4.6
通讯作者：
Misaka T
中科院分区：
文献类型：
--
作者：
Toda Y;Nakagita T;Hirokawa T;Yamashita Y;Nakajima A;Narukawa M;Ishimaru Y;Uchida R;Misaka T
味觉是脊椎动物的一种重要感觉，能够检测营养重要的物质或潜在的毒素。两个C类GPCR T1 R1和T1 R3的异聚复合物被鉴定为鲜味（咸味）味觉受体。众所周知，氨基酸和5′-核糖核苷酸是人T1 R1/T1 R3的天然配体。在这项研究中，我们发现，蛋氨酸，这是一个熟悉的风味成分的食品，是一个变构调制器T1 R1/T1 R3。受体表达实验表明，蛋氨酸作为一个积极的变构调节剂（PAM）的人T1 R1/T1 R3和作为一个负变构调节剂（NAM）的小鼠T1 R1/T1 R3。尽管氨基酸和5′-核糖核苷酸与T1 R1的胞外结构域结合，但种间嵌合受体的使用表明蛋氨酸与T1 R1的跨膜结构域相互作用。定点突变和分子模拟结果表明，甲硫氨酸可能与T1 R1跨膜区的两个不同位点结合，并且T1 R1变构口袋底部的氨基酸残基引起了PAM和NAM模式的转换，这可能有助于甲硫氨酸结合位置的转换。这些结果可能适用于阐明其他C类GPCR识别配体的分子机制。
Taste is a vital sensation for vertebrates, enabling the detection of nutritionally important substances or potential toxins. A heteromeric complex of two class C GPCRs, T1R1 and T1R3, was identified as the umami (savory) taste receptor. Amino acids and 5′-ribonucleotides are well known to be natural ligands for human T1R1/T1R3. In this study, we reveal that methional, which is a familiar flavor component in foods, is an allosteric modulator of T1R1/T1R3. Receptor expression experiments showed that methional served as a positive allosteric modulator (PAM) of human T1R1/T1R3 and functioned as a negative allosteric modulator (NAM) of mouse T1R1/T1R3. Although amino acids and 5′-ribonucleotides bound to the extracellular domain of T1R1, the use of interspecies chimeric receptors demonstrated that methional interacted with the transmembrane domain of T1R1. Site-directed mutagenesis and molecular modeling showed that methional could potentially bind at two distinct sites in the transmembrane domain of T1R1 and that the amino acid residues in the bottom of the allosteric pocket engendered the switch between the PAM and NAM modes, which could contribute to switching the binding position of methional. These results may be applicable for elucidating the molecular mechanisms underlying ligand recognition by other class C GPCRs.
登录
查看更多内容
DOI：
10.1038/nrd2760
发表时间：
2009-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
影响因子：
6.1
作者：
Mayer, Florian;Takeoka, Gary R.;Rabinowitch, Haim D.
通讯作者：
Rabinowitch, Haim D.
影响因子：
6.1
作者：
Milo, C;Reineccius, GA
通讯作者：
Reineccius, GA
影响因子：
3.5
作者：
Soldo, T;Blank, I;Hofmann, T
通讯作者：
Hofmann, T
T1R1/T1R3（鲜味的味觉受体）中配体特异性的两个不同决定因素。
DOI：
10.1074/jbc.m113.494443
发表时间：
2013-12-27
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Toda Y;Nakagita T;Hayakawa T;Okada S;Narukawa M;Imai H;Ishimaru Y;Misaka T
通讯作者：
Misaka T