Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation.
Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation.
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活性态食欲素受体2的结构使肽和小分子激动剂识别和受体活化合理化。
DOI：
10.1038/s41467-021-21087-6
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发表时间：
2021-02-05
影响因子：
16.6
通讯作者：
Hollenstein K
中科院分区：
文献类型：
--
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
1型嗜睡症(NT1)是一种慢性神经系统疾病，损害了大脑控制睡眠-觉醒周期的能力。目前的治疗方法仅限于对症状的管理，疗效不高，副作用很大。食欲素受体2(OX2R)的激动剂已显示出作为直接针对疾病病理生理学的新疗法的前景。然而，鉴定类药物OX2R激动剂已被证明是困难的。在这里，我们报告了与内源性多肽激动剂和小分子激动剂结合的活性状态OX2R的冷冻电子显微镜结构。肽的延伸的羧基末端片段到达OX2R的核心以稳定活性构象，而小分子激动剂结合到正位口袋的深处，进行类似的关键相互作用。与拮抗剂结合的OX2R相比，表明了一种使受体激活和抑制合理化的分子机制。我们的结果使基于结构的发现治疗性食欲素激动剂治疗NT1和其他睡眠障碍成为可能。食欲素受体2(OX2R)激动剂在治疗发作性睡病方面显示出良好的前景。结合内源性多肽激动剂和小分子激动剂的活性状态OX2R的冷冻-EM结构表明了一种使受体激活和抑制合理化的分子机制。
Narcolepsy type 1 (NT1) is a chronic neurological disorder that impairs the brain’s ability to control sleep-wake cycles. Current therapies are limited to the management of symptoms with modest effectiveness and substantial adverse effects. Agonists of the orexin receptor 2 (OX2R) have shown promise as novel therapeutics that directly target the pathophysiology of the disease. However, identification of drug-like OX2R agonists has proven difficult. Here we report cryo-electron microscopy structures of active-state OX2R bound to an endogenous peptide agonist and a small-molecule agonist. The extended carboxy-terminal segment of the peptide reaches into the core of OX2R to stabilize an active conformation, while the small-molecule agonist binds deep inside the orthosteric pocket, making similar key interactions. Comparison with antagonist-bound OX2R suggests a molecular mechanism that rationalizes both receptor activation and inhibition. Our results enable structure-based discovery of therapeutic orexin agonists for the treatment of NT1 and other hypersomnia disorders. Agonists of the orexin receptor 2 (OX2R) show promise in the treatment of narcolepsy. Cryo-EM structures of active-state OX2R bound to an endogenous peptide agonist and a small-molecule agonist suggest a molecular mechanism that rationalizes both receptor activation and inhibition.
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影响因子：
2.9
作者：
Heifetz, Alexander;Barker, Oliver;Morris, G. Benjamin;Law, Richard J.;Slack, Mark;Biggin, Philip C.
通讯作者：
Biggin, Philip C.
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
使用碎片分子轨道方法研究激动剂 - 蛋白质-2受体相互作用。
影响因子：
3.9
作者：
Heifetz A;Aldeghi M;Chudyk EI;Fedorov DG;Bodkin MJ;Biggin PC
通讯作者：
Biggin PC
DOI：
10.1093/protein/gzw049
发表时间：
2016-12
期刊：
Protein engineering, design & selection : PEDS
影响因子：
--
作者：
Carpenter B;Tate CG
通讯作者：
Tate CG
影响因子：
0.2
作者：
Dubey AK;Handu SS;Mediratta PK
通讯作者：
Mediratta PK