Structural basis for the ligand recognition and signaling of free fatty acid receptors.
Structural basis for the ligand recognition and signaling of free fatty acid receptors.
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DOI：
10.1126/sciadv.adj2384
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发表时间：
2024-01-12
期刊：
影响因子：
13.6
通讯作者：
Zhang, Cheng
中科院分区：
文献类型：
--
作者：
Zhang, Xuan;Guseinov, Abdul-Akim;Jenkins, Laura;Li, Kunpeng;Tikhonova, Irina G.;Milligan, Graeme;Zhang, Cheng
游离脂肪酸受体1至4（FFA 1至FFA 4）是A类G蛋白偶联受体（GPCR）。FFA 1与FFA 3具有实质性的序列相似性，而FFA 4不相关。然而，FFA 1和FFA 4被长链脂肪酸激活，而FFA 2和FFA 3对肠道微生物群产生的短链脂肪酸做出反应。FFA 1、FFA 2和FFA 4是代谢和炎症疾病的潜在药物靶点。在这里，我们通过冷冻电子显微镜确定了与二十二碳六烯酸结合的FFA 1和FFA 4、与合成激动剂TUG-891结合的FFA 4和与丁酸盐结合的FFA 2的活性结构，每个结构都与工程异源三聚体Gq蛋白（miniGq）复合。结合计算机模拟和诱变研究，我们阐明了脂肪酸配体与其各自GPCR结合模式的相似性和差异性。我们的研究结果揭示了受体激活和G蛋白偶联的不同机制。我们预计，这些结果将促进基于结构的药物开发，并支持未来对这组GPCR的研究。游离脂肪酸受体信号复合物的结构揭示了配体识别和受体活化的机制。
Free fatty acid receptors 1 to 4 (FFA1 to FFA4) are class A G protein–coupled receptors (GPCRs). FFA1 to FFA3 share substantial sequence similarity, whereas FFA4 is unrelated. However, FFA1 and FFA4 are activated by long-chain fatty acids, while FFA2 and FFA3 respond to short-chain fatty acids generated by intestinal microbiota. FFA1, FFA2, and FFA4 are potential drug targets for metabolic and inflammatory conditions. Here, we determined the active structures of FFA1 and FFA4 bound to docosahexaenoic acid, FFA4 bound to the synthetic agonist TUG-891, and butyrate-bound FFA2, each complexed with an engineered heterotrimeric Gq protein (miniGq), by cryo–electron microscopy. Together with computational simulations and mutagenesis studies, we elucidated the similarities and differences in the binding modes of fatty acid ligands to their respective GPCRs. Our findings unveiled distinct mechanisms of receptor activation and G protein coupling. We anticipate that these outcomes will facilitate structure-based drug development and underpin future research on this group of GPCRs. Structures of free fatty acid receptor signaling complexes reveal mechanisms of ligand recognition and receptor activation.
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DOI：
10.1096/fj.12-213314
发表时间：
2012-12
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
--
作者：
Hudson BD;Christiansen E;Tikhonova IG;Grundmann M;Kostenis E;Adams DR;Ulven T;Milligan G
通讯作者：
Milligan G
影响因子：
5.5
作者：
Dickson, Callum J.;Walker, Ross C.;Gould, Ian R.
通讯作者：
Gould, Ian R.
影响因子：
18.2
作者：
Ciancetta A;Gill AK;Ding T;Karlov DS;Chalhoub G;McCormick PJ;Tikhonova IG
通讯作者：
Tikhonova IG
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
7.3
作者：
Hansen, Anders Hojgaard;Sergeev, Eugenia;Ulven, Trond
通讯作者：
Ulven, Trond