Molecular recognition of formylpeptides and diverse agonists by the formylpeptide receptors FPR1 and FPR2.
Molecular recognition of formylpeptides and diverse agonists by the formylpeptide receptors FPR1 and FPR2.
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DOI：
10.1038/s41467-022-28586-0
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发表时间：
2022-02-25
影响因子：
16.6
通讯作者：
Zhang C
中科院分区：
文献类型：
--
作者：
Zhuang Y;Wang L;Guo J;Sun D;Wang Y;Liu W;Xu HE;Zhang C
甲酰肽受体（FPRs）介导来自入侵病原体或来自死亡宿主细胞的线粒体的甲酰化肽的模式识别。它们还可以感知其他结构不同的天然肽，甚至脂质介质，以促进或解决炎症。FPR的药理学靶向代表了治疗炎性疾病的新的治疗方法。然而，FPR配体识别的分子机制是难以捉摸的。我们报告了与甲酰基肽结合的GI偶联FPR 1和FPR 2以及与两种合成肽和小分子激动剂结合的GI偶联FPR 2的冷冻电镜结构。连同诱变数据，我们的结构揭示了FPRs和FPR 1和FPR 2的结构变异导致其不同的配体偏好的甲酰肽识别的分子机制。结构分析还表明，不同的FPR激动剂样本的配体结合口袋底部的保守激活室激活FPR。研究结果为FPR的合理药物设计提供了依据。Zhuang等人报道了与Gi蛋白和不同激动剂偶联的甲酰肽受体FPR 1和FPR 2的四种冷冻-EM结构，揭示了FPR作为模式识别受体如何识别甲酰肽和合成激动剂以及独特的受体激活机制。
The formylpeptide receptors (FPRs) mediate pattern recognition of formylated peptides derived from invading pathogens or mitochondria from dead host cells. They can also sense other structurally distinct native peptides and even lipid mediators to either promote or resolve inflammation. Pharmacological targeting of FPRs represents a novel therapeutic approach in treating inflammatory diseases. However, the molecular mechanisms underlying FPR ligand recognition are elusive. We report cryo-EM structures of Gi-coupled FPR1 and FPR2 bound to a formylpeptide and Gi-coupled FPR2 bound to two synthetic peptide and small-molecule agonists. Together with mutagenesis data, our structures reveal the molecular mechanism of formylpeptide recognition by FPRs and structural variations of FPR1 and FPR2 leading to their different ligand preferences. Structural analysis also suggests that diverse FPR agonists sample a conserved activation chamber at the bottom of ligand-binding pockets to activate FPRs. Our results provide a basis for rational drug design on FPRs. Zhuang et al. report four cryo-EM structures of formylpeptide receptors FPR1 and FPR2 coupled with Gi protein and diverse agonists, revealing how FPRs as pattern recognition receptors recognize formylpeptides and synthetic agonists and a distinctive receptor activation mechanism.
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影响因子：
48
作者：
Kucukelbir, Alp;Sigworth, Fred J.;Tagare, Hemant D.
通讯作者：
Tagare, Hemant D.
影响因子：
64.8
作者：
Koehl A;Hu H;Maeda S;Zhang Y;Qu Q;Paggi JM;Latorraca NR;Hilger D;Dawson R;Matile H;Schertler GFX;Granier S;Weis WI;Dror RO;Manglik A;Skiniotis G;Kobilka BK
通讯作者：
Kobilka BK
影响因子：
16.6
作者：
Hong C;Byrne NJ;Zamlynny B;Tummala S;Xiao L;Shipman JM;Partridge AT;Minnick C;Breslin MJ;Rudd MT;Stachel SJ;Rada VL;Kern JC;Armacost KA;Hollingsworth SA;O'Brien JA;Hall DL;McDonald TP;Strickland C;Brooun A;Soisson SM;Hollenstein K
通讯作者：
Hollenstein K
影响因子：
3.7
作者：
Klarenbeek J;Goedhart J;van Batenburg A;Groenewald D;Jalink K
通讯作者：
Jalink K
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