Molecular mechanism of biased signaling at the kappa opioid receptor.
Molecular mechanism of biased signaling at the kappa opioid receptor.
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DOI：
10.1038/s41467-023-37041-7
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发表时间：
2023-03-11
影响因子：
16.6
通讯作者：
Che, Tao
中科院分区：
文献类型：
--
作者：
El Daibani, Amal;Paggi, Joseph M. M.;Kim, Kuglae;Laloudakis, Yianni D. D.;Popov, Petr D.;Bernhard, Sarah M. M.;Krumm, Brian E. E.;Olsen, Reid H. J.;Diberto, Jeffrey;Carroll, F. Ivy;Katritch, Vsevolod;Wuensch, Bernhard;Dror, Ron O. O.;Che, Tao
κ-阿片受体（KOR）已成为无成瘾性疼痛管理的有吸引力的药物靶标，通过KOR特定途径的偏倚信号传导可能是维持这种益处同时最大限度地减少副作用的关键。然而，对于大多数G蛋白偶联受体（GPCRs），KOR的配体特异性信号传导的分子机制仍不清楚。为了更好地了解KOR信号偏差的分子决定因素，我们应用结构测定，原子水平的分子动力学（MD）模拟和功能测定。我们确定了与G蛋白偏向激动剂纳呋拉芬（第一个批准的KOR靶向药物）结合的KOR晶体结构。我们还确定了抑制蛋白偏向KOR激动剂，WMS-X600。使用MD模拟的KOR结合纳呋拉芬，WMS-X600，和一个平衡的激动剂U 50，488，我们确定了三个活跃状态的受体构象，包括一个似乎有利于抑制蛋白信号传导超过G蛋白信号传导，另一个似乎有利于G蛋白信号传导超过抑制蛋白信号传导。这些结果，结合诱变验证，提供了一个分子解释激动剂如何实现偏置信号在KOR。κ-阿片受体（KOR）中的偏性信号传导为疼痛管理提供了一种有吸引力的策略。在这里，作者确定KOR信号偏差的决定因素结合分子动力学模拟使用的结构方法。
The κ-opioid receptor (KOR) has emerged as an attractive drug target for pain management without addiction, and biased signaling through particular pathways of KOR may be key to maintaining this benefit while minimizing side-effect liabilities. As for most G protein-coupled receptors (GPCRs), however, the molecular mechanisms of ligand-specific signaling at KOR have remained unclear. To better understand the molecular determinants of KOR signaling bias, we apply structure determination, atomic-level molecular dynamics (MD) simulations, and functional assays. We determine a crystal structure of KOR bound to the G protein-biased agonist nalfurafine, the first approved KOR-targeting drug. We also identify an arrestin-biased KOR agonist, WMS-X600. Using MD simulations of KOR bound to nalfurafine, WMS-X600, and a balanced agonist U50,488, we identify three active-state receptor conformations, including one that appears to favor arrestin signaling over G protein signaling and another that appears to favor G protein signaling over arrestin signaling. These results, combined with mutagenesis validation, provide a molecular explanation of how agonists achieve biased signaling at KOR. Biased signaling in κ-opiod receptors (KOR) offer an attractive strategy for pain management. Here the authors identify determinants of KOR signaling bias using structural methods in combination with molecular dynamics simulations.
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影响因子：
7.3
作者：
Ho JH;Stahl EL;Schmid CL;Scarry SM;Aubé J;Bohn LM
通讯作者：
Bohn LM
影响因子：
64.8
作者：
Eichel K;Jullié D;Barsi-Rhyne B;Latorraca NR;Masureel M;Sibarita JB;Dror RO;von Zastrow M
通讯作者：
von Zastrow M
DOI：
10.1073/pnas.90.21.10206
发表时间：
1993-11-01
影响因子：
11.1
作者：
FAHMY, K;JAGER, F;SIEBERT, F
通讯作者：
SIEBERT, F
影响因子：
16.6
作者：
Che, Tao;English, Justin;Roth, Bryan L.
通讯作者：
Roth, Bryan L.
影响因子：
64.8
作者：
Huang W;Manglik A;Venkatakrishnan AJ;Laeremans T;Feinberg EN;Sanborn AL;Kato HE;Livingston KE;Thorsen TS;Kling RC;Granier S;Gmeiner P;Husbands SM;Traynor JR;Weis WI;Steyaert J;Dror RO;Kobilka BK
通讯作者：
Kobilka BK