Cell Discovery：催乳素释放肽通过其G蛋白偶联受体识别和信号传导的分子机制-动脉网

Cell Discovery：Molecular mechanism of prolactin-releasing peptide recognition and signaling via its G protein-coupled receptor

Nature 等信源发布 2024-09-03 13:42

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AbstractProlactin-releasing peptide (PrRP) is an RF-amide neuropeptide that binds and activates its cognate G protein-coupled receptor, prolactin-releasing peptide receptor (PrRPR), also known as GPR10. PrRP and PrRPR are highly conserved across mammals and involved in regulating a range of physiological processes, including stress response, appetite regulation, pain modulation, cardiovascular function, and potentially reproductive functions.

催乳素释放肽（PrRP）是一种RF酰胺神经肽，可结合并激活其同源G蛋白偶联受体催乳素释放肽受体（PrRPR），也称为GPR10。PrRP和PrRP在哺乳动物中高度保守，并参与调节一系列生理过程，包括应激反应，食欲调节，疼痛调节，心血管功能和潜在的生殖功能。

Here we present cryo-electron microscopy structures of PrRP-bound PrRPR coupled to Gq or Gi heterotrimer, unveiling distinct molecular determinants underlying the specific recognition of the ligand’s C-terminal RF-amide motif. We identify a conserved polar pocket that accommodates the C-terminal amide shared by RF-amide peptides.

在这里，我们介绍了与Gq或Gi异源三聚体偶联的PrRP结合的PrRPR的低温电子显微镜结构，揭示了配体C端RF酰胺基序特异性识别的不同分子决定因素。我们确定了一个保守的极性口袋，该口袋容纳RF酰胺肽共有的C端酰胺。

Structural comparison with neuropeptide Y receptors reveals both similarities and differences in engaging the essential RF/RY-amide motifs. Our findings demonstrate the general mechanism governing RF-amide motif recognition by PrRPR and RF-amide peptide receptors, and provide a foundation for elucidating activation mechanisms and developing selective drugs targeting this important peptide–receptor system..

与神经肽Y受体的结构比较揭示了参与必需RF/RY酰胺基序的相似性和差异性。我们的发现证明了PrRPR和RF酰胺肽受体识别RF酰胺基序的一般机制，并为阐明激活机制和开发针对这一重要肽受体系统的选择性药物奠定了基础。。

IntroductionNeuropeptides, with over 100 identified types, are the most abundant signaling molecules in the nervous system. Among these, RF-amide peptides, identifiable by their C-terminal Arg-Phe-NH2 (RF-amide) motif, play vital roles as neurotransmitters and neuromodulators. They are involved in a range of physiological processes, including metabolism, pain perception, and reproduction1.

简介神经肽是神经系统中最丰富的信号分子，有100多种已鉴定的类型。其中，通过其C端Arg-Phe-NH2（RF酰胺）基序可识别的RF酰胺肽作为神经递质和神经调节剂起着至关重要的作用。。

In mammals, the RF-amide peptide subfamily comprises prolactin-releasing peptide (PrRP), neuropeptide FF (NPFF), kisspeptin, RF-amide-related peptide (RFRP), and pyroglutamylated RF-amide peptide (QRFP). These neuropeptides interact with five G protein-coupled receptors (GPCRs): prolactin-releasing peptide receptor (PrRPR, GPR10)2, neuropeptide FF receptor 1/2 (NPFF1R/NPFF2R, GPR147/GPR74)3,4, kisspeptin receptor (KISS1R, GPR54)5, and pyroglutamylated RF-amide peptide receptor (QRFPR, GPR103)6.

在哺乳动物中，RF酰胺肽亚家族包含催乳素释放肽（PrRP），神经肽FF（NPFF），kisspeptin，RF酰胺相关肽（RFRP）和焦谷氨酰化RF酰胺肽（QRFP）。这些神经肽与五种G蛋白偶联受体（GPCR）相互作用：催乳素释放肽受体（PrRPR，GPR10）2，神经肽FF受体1/2（NPFF1R/NPFF2R，GPR147/GPR74）3,4，kisspeptin受体（KISS1R，GPR54）5和焦谷氨酰化RF酰胺肽受体（QRFPR，GPR103）6。

Notably, PrRP and PrRPR are highly conserved across mammals and are integral in regulating behaviors and physiological processes through the endocrine system.PrRP, first isolated from bovine hypothalamus, has two biologically active isoforms, PrRP31 and PrRP20. PrRP20 is a 20-amino acid peptide with amidation at its C-terminus (Fig.

值得注意的是，PrRP和PrRPR在哺乳动物中高度保守，并且在通过内分泌系统调节行为和生理过程中是不可或缺的。PrRP首先从牛下丘脑中分离出来，具有两种生物活性同工型，PrRP31和PrRP20。PrRP20是一种20个氨基酸的肽，在其C端具有酰胺化作用（图）。

1a)2. Identified as the endogenous ligand for GPR10 through reverse pharmacology, PrRP20 shows a high affinity to this receptor2,7. PrRPR, primarily triggering Gq/11 signaling pathways, is also suggested to engage Gi/o pathways (Fig. 1b)8. PrRPR is abundantly expressed in the thalamic reticular nucleus, hypothalamic nuclei, area postrema, and nucleus of the solitary tract9,10.

1a）2。通过反向药理学鉴定为GPR10的内源性配体，PrRP20对该受体显示出高亲和力2,7。。PrRPR在丘脑网状核，下丘脑核，后区和孤束核中大量表达9,10。

These regions regulate functions like stress, appetite, pain and reproduction. Though initially posited to govern prolactin release, prevailing evidence suggests that PrRP/PrRPR regulate food .

这些区域调节压力、食欲、疼痛和生殖等功能。尽管最初被认为可以控制催乳素的释放，但普遍的证据表明PrRP/PrRPR可以调节食物。

Data availability

数据可用性

The atomic coordinates and the electron microscopy maps have been deposited in the Protein Data Bank (PDB) and the Electron Microscopy Data Back (EMDB) under accession numbers: 8ZPT and EMD-60354 for the PrRP20–PrRPR–Gq complex, 8ZPS and EMD-60353 for the PrRP20–PrRPR–Gi complex.

原子坐标和电子显微镜图已保存在蛋白质数据库（PDB）和电子显微镜数据（EMDB）中，登录号为：PrRP20-PrRPR-Gq复合物的8ZPT和EMD-60354，PrRP20-PrRPR-Gi复合物的8ZPS和EMD-60353。

ReferencesQuillet, R. et al. RF-amide neuropeptides and their receptors in mammals: pharmacological properties, drug development and main physiological functions. Pharmacol. Therap. 160, 84–132 (2016).Article

参考文献Quillet，R。等人。哺乳动物中的RF酰胺神经肽及其受体：药理学特性，药物开发和主要生理功能。药理学。治疗。160,84-132（2016）。文章

CAS

中科院

Google Scholar

谷歌学者

Hinuma, S. et al. A prolactin-releasing peptide in the brain. Nature 393, 272–276 (1998).Article

Hinuma，S。等人。大脑中的催乳素释放肽。自然393272-276（1998）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Bonini, J. A. et al. Identification and characterization of two G protein-coupled receptors for neuropeptide FF. J. Biol. Chem. 275, 39324–39331 (2000).Article

Bonini，J.A。等人。神经肽FF.J.Biol的两种G蛋白偶联受体的鉴定和表征。。27539324-39331（2000）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Elshourbagy, N. A. et al. Receptor for the pain modulatory neuropeptides FF and AF is an orphan G protein-coupled receptor. J. Biol. Chem. 275, 25965–25971 (2000).Article

Elshourbagy，N.A。等人，疼痛调节神经肽FF和AF的受体是一种孤儿G蛋白偶联受体。J、生物。。。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Kotani, M. et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J. Biol. Chem. 276, 34631–34636 (2001).Article

转移抑制基因KiSS-1编码kisspeptins，这是孤儿G蛋白偶联受体GPR54的天然配体。J、生物。。27634631–34636（2001）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Chartrel, N. et al. Identification of 26RFa, a hypothalamic neuropeptide of the RFamide peptide family with orexigenic activity. Proc. Natl. Acad. Sci. USA 100, 15247–15252 (2003).Article

Chartrel，N。等人。鉴定26RFa，一种具有促食欲活性的RFamide肽家族的下丘脑神经肽。程序。纳特尔。阿卡德。科学。美国10015247–15252（2003）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Welch, S. K., O’Hara, B. F., Kilduff, T. S. & Heller, H. C. Sequence and tissue distribution of a candidate G-coupled receptor cloned from rat hypothalamus. Biochem. Biophys. Res. Commun. 209, 606–613 (1995).Article

Welch，S.K.，O'Hara，B.F.，Kilduff，T.S。＆Heller，H.C。从大鼠下丘脑克隆的候选G偶联受体的序列和组织分布。生物化学。生物物理。公共资源。209606-613（1995）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Kimura, A. et al. Prolactin-releasing peptide activation of the prolactin promoter is differentially mediated by extracellular signal-regulated protein kinase and c-Jun N-terminal protein kinase. J. Biol. Chem. 275, 3667–3674 (2000).Article

Kimura，A。等人。催乳素启动子的催乳素释放肽激活是由细胞外信号调节蛋白激酶和c-Jun N端蛋白激酶差异介导的。J、生物。。2753667-3674（2000）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Roland, B. L. et al. Anatomical distribution of prolactin-releasing peptide and its receptor suggests additional functions in the central nervous system and periphery. Endocrinology 140, 5736–5745 (1999).Article

泌乳素释放肽及其受体的解剖学分布表明，其在中枢神经系统和外周具有其他功能。内分泌学1405736-5745（1999）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Ibata, Y. et al. Morphological survey of prolactin-releasing peptide and its receptor with special reference to their functional roles in the brain. Neurosci. Res. 38, 223–230 (2000).Article

Ibata，Y.等人。催乳素释放肽及其受体的形态学调查，特别是它们在大脑中的功能作用。神经科学。第38223-230号决议（2000年）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Lawrence, C. B., Celsi, F., Brennand, J. & Luckman, S. M. Alternative role for prolactin-releasing peptide in the regulation of food intake. Nat. Neurosci. 3, 645–646 (2000).Article

Lawrence，C.B.，Celsi，F.，Brennand，J。＆Luckman，S.M。催乳素释放肽在调节食物摄入中的替代作用。自然神经科学。3645-646（2000）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Lawrence, C. B., Ellacott, K. L. & Luckman, S. M. PRL-releasing peptide reduces food intake and may mediate satiety signaling. Endocrinology 143, 360–367 (2002).Article

Lawrence，C.B.，Ellacott，K.L。和Luckman，S.M。PRL释放肽减少食物摄入并可能介导饱腹感信号传导。内分泌学143360-367（2002）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Kalliomäki, M. L. et al. Prolactin-releasing peptide affects pain, allodynia and autonomic reflexes through medullary mechanisms. Neuropharmacology 46, 412–424 (2004).Article

Kalliomäki，M.L.等人。催乳素释放肽通过髓质机制影响疼痛，异常性疼痛和自主神经反射。神经药理学46412-424（2004）。文章

PubMed

Google Scholar

谷歌学者

Maruyama, M. et al. Prolactin-releasing peptide as a novel stress mediator in the central nervous system. Endocrinology 142, 2032–2038 (2001).Article

Maruyama，M。等人。催乳素释放肽作为中枢神经系统中的新型应激介质。。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Iijima, N. et al. A novel function of prolactin-releasing peptide in the control of growth hormone via secretion of somatostatin from the hypothalamus. Endocrinology 142, 3239–3243 (2001).Article

Iijima，N。等人。催乳素释放肽通过下丘脑分泌生长抑素来控制生长激素的新功能。内分泌学1423239-3243（2001）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Zhang, S. Q., Kimura, M. & Inoué, S. Effects of prolactin-releasing peptide (PrRP) on sleep regulation in rats. Psychiatry Clin. Neurosci. 54, 262–264 (2000).Article

Zhang，S.Q.，Kimura，M。＆Inoué，S。催乳素释放肽（PrRP）对大鼠睡眠调节的影响。精神病学临床。神经科学。54262-264（2000）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Zhang, S. Q., Inoué, S. & Kimura, M. Sleep-promoting activity of prolactin-releasing peptide (PrRP) in the rat. Neuroreport 12, 3173–3176 (2001).Article

Zhang，S.Q.，Inoué，S。＆Kimura，M。催乳素释放肽（PrRP）在大鼠中的睡眠促进活性。神经报告123173-3176（2001）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Špolcová, A. et al. Anorexigenic lipopeptides ameliorate central insulin signaling and attenuate tau phosphorylation in hippocampi of mice with monosodium glutamate-induced obesity. J. Alzheimer’s. Dis. 45, 823–835 (2015).Article

Špolcová，A。等人。产生厌食的脂肽可改善中枢胰岛素信号传导，并减弱谷氨酸钠诱导的肥胖小鼠海马中tau蛋白的磷酸化。J、阿尔茨海默氏症。Dis。45823-835（2015）。文章

Google Scholar

谷歌学者

Popelová, A. et al. Novel lipidized analog of prolactin-releasing peptide improves memory impairment and attenuates hyperphosphorylation of tau protein in a mouse model of tauopathy. J. Alzheimer’s. Dis. 62, 1725–1736 (2018).Article

Popelová，A。等人。在tau蛋白病小鼠模型中，催乳素释放肽的新型脂质化类似物可改善记忆障碍并减弱tau蛋白的过度磷酸化。J、阿尔茨海默氏症。Dis。621725-1736（2018）。文章

Google Scholar

谷歌学者

Holubová, M. et al. Liraglutide and a lipidized analog of prolactin-releasing peptide show neuroprotective effects in a mouse model of β-amyloid pathology. Neuropharmacology 144, 377–387 (2019).Article

Holubová，M。等人，利拉鲁肽和催乳素释放肽的脂质类似物在β-淀粉样蛋白病理学的小鼠模型中显示出神经保护作用。神经药理学144377-387（2019）。文章

PubMed

Google Scholar

谷歌学者

Boyle, R. G. et al. Structure-activity studies on prolactin-releasing peptide (PrRP). Analogues of PrRP-(19-31)-peptide. J. Pept. Sci. 11, 161–165 (2005).Article

Boyle，R.G.等人。催乳素释放肽（PrRP）的结构活性研究。PrRP-（19-31）-肽的类似物。J、佩普。科学。11161-165（2005）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Mráziková, L. et al. Lipidized prolactin-releasing peptide as a new potential tool to treat obesity and type 2 diabetes mellitus: preclinical studies in rodent models. Front. Pharmacol. 12, 779962 (2021).Article

áziková先生，L.等人。脂质化催乳素释放肽作为治疗肥胖和2型糖尿病的新潜在工具：啮齿动物模型的临床前研究。正面。药理学。12779962（2021）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Kuneš, J. et al. Prolactin-releasing peptide: a new tool for obesity treatment. J. Endocrinol. 230, R51–R58 (2016).Article

Kuneš，J.等。催乳素释放肽：肥胖治疗的新工具。J、内分泌。230，R51–R58（2016）。文章

PubMed

Google Scholar

谷歌学者

Engström, M., Brandt, A., Wurster, S., Savola, J. M. & Panula, P. Prolactin releasing peptide has high affinity and efficacy at neuropeptide FF2 receptors. J. Pharmacol. Exp. Therap. 305, 825–832 (2003).Article

Engström，m.，Brandt，A.，Wurster，S.，Savola，J.m。＆Panula，P。催乳素释放肽对神经肽FF2受体具有高亲和力和功效。J、药理学。实验治疗。305825-832（2003）。文章

Google Scholar

谷歌学者

Bruzzone, F. et al. Distribution of 26RFa binding sites and GPR103 mRNA in the central nervous system of the rat. J. Comp. Neurol. 503, 573–591 (2007).Article

Bruzzone，F。等人。大鼠中枢神经系统中26RFa结合位点和GPR103 mRNA的分布。J、公司。神经病学。503573-591（2007）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Oishi, S. et al. Activation of neuropeptide FF receptors by kisspeptin receptor ligands. ACS Med. Chem. Lett. 2, 53–57 (2011).Article

Oishi，S。等人。kisspeptin受体配体激活神经肽FF受体。。利特。2，53-57（2011）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Zhao, F. et al. Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors. Nat. Commun. 13, 1057 (2022).Article

Zhao，F。等人。关于替罗西肽和肽20在GIP，GLP-1或胰高血糖素受体上的多重药理作用的结构见解。。131057（2022）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Duan, J. et al. Cryo-EM structure of an activated VIP1 receptor-G protein complex revealed by a NanoBiT tethering strategy. Nat. Commun. 11, 4121 (2020).Article

Duan，J。等人。通过纳米位束缚策略揭示的活化的VIP1受体-G蛋白复合物的低温EM结构。。114121（2020）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Zhao, L. H. et al. Structure insights into selective coupling of G protein subtypes by a class B G protein-coupled receptor. Nat. Commun. 13, 6670 (2022).Article

。。136670（2022年）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Nehmé, R. et al. Mini-G proteins: Novel tools for studying GPCRs in their active conformation. PLoS One 12, e0175642 (2017).Article

Nehmé，R。等人。Mini-G蛋白：研究GPCR活性构象的新工具。。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Rasmussen, S. G. et al. Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature 477, 549–555 (2011).Article

Rasmussen，S.G.等人。β2肾上腺素能受体Gs蛋白复合物的晶体结构。自然477549-555（2011）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Deluca, S. H., Rathmann, D., Beck-Sickinger, A. G. & Meiler, J. The activity of prolactin releasing peptide correlates with its helicity. Biopolymers 99, 314–325 (2013).Article

Deluca，S.H.，Rathmann，D.，Beck Sickinger，A.G。＆Meiler，J。催乳素释放肽的活性与其螺旋度相关。生物聚合物99314-325（2013）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

D’Ursi, A. M. et al. Structural studies on Hgr3 orphan receptor ligand prolactin-releasing peptide. J. Med. Chem. 45, 5483–5491 (2002).Article

D'Ursi，A.M.等人。Hgr3孤儿受体配体催乳素释放肽的结构研究。J、医学化学。455483-5491（2002）。文章

PubMed

Google Scholar

谷歌学者

Bader, R., Bettio, A., Beck-Sickinger, A. G. & Zerbe, O. Structure and dynamics of micelle-bound neuropeptide Y: comparison with unligated NPY and implications for receptor selection. J. Mol. Biol. 305, 307–329 (2001).Article

Bader，R.，Bettio，A.，Beck-Sickinger，A.G。＆Zerbe，O。胶束结合神经肽Y的结构和动力学：与未连接NPY的比较以及对受体选择的影响。J、。305307-329（2001）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Tang, T. et al. Receptor-specific recognition of NPY peptides revealed by structures of NPY receptors. Sci. Adv. 8, eabm1232 (2022).Article

Tang，T。等人。NPY受体结构揭示的NPY肽的受体特异性识别。科学。广告8，eabm1232（2022）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Maletínská, L., Spolcová, A., Maixnerová, J., Blechová, M. & Zelezná, B. Biological properties of prolactin-releasing peptide analogs with a modified aromatic ring of a C-terminal phenylalanine amide. Peptides 32, 1887–1892 (2011).Article

Maletínská，L.，Spolcová，A.，Maixnerová，J.，Blechová，M.和Zelezná，B.具有C末端苯丙氨酸酰胺修饰芳环的催乳素释放肽类似物的生物学性质。肽321887-1892（2011）。文章

PubMed

Google Scholar

谷歌学者

Park, C. et al. Structural basis of neuropeptide Y signaling through Y1 receptor. Nat. Commun. 13, 853 (2022).Article

Park，C.等人。通过Y1受体的神经肽Y信号传导的结构基础。。13853（2022）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Flock, T. et al. Universal allosteric mechanism for Gα activation by GPCRs. Nature 524, 173–179 (2015).Article

Flock，T。等人。GPCR激活Gα的通用变构机制。《自然》524173-179（2015）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

García-Nafría, J., Nehmé, R., Edwards, P. C. & Tate, C. G. Cryo-EM structure of the serotonin 5-HT(1B) receptor coupled to heterotrimeric G(o). Nature 558, 620–623 (2018).Article

García-Nafría，J.，Nehmé，R.，Edwards，P.C。＆Tate，C.G。与异源三聚体G（o）偶联的5-羟色胺5-HT（1B）受体的低温EM结构。自然558620-623（2018）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Kim, H. R. et al. Structural mechanism underlying primary and secondary coupling between GPCRs and the Gi/o family. Nat. Commun. 11, 3160 (2020).Article

Kim，H.R.等人。GPCR与Gi/o家族之间一级和二级耦合的结构机制。。113160（2020）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Kim, K. et al. Structure of a hallucinogen-activated Gq-coupled 5-HT(2A) serotonin receptor. Cell 182, 1574–1588.e19 (2020).Article

Kim，K.等人。迷幻剂激活的Gq偶联的5-HT（2A）血清素受体的结构。。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Wang, Y. et al. Molecular recognition of an acyl-peptide hormone and activation of ghrelin receptor. Nat. Commun. 12, 5064 (2021).Article

Wang，Y.等人。酰基肽激素的分子识别和生长素释放肽受体的激活。。125064（2021）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Yin, Y. L. et al. Molecular basis for kinin selectivity and activation of the human bradykinin receptors. Nat. Struct. Mol. Biol. 28, 755–761 (2021).Article

Yin，Y.L.等人。激肽选择性和人类缓激肽受体激活的分子基础。自然结构。分子生物学。28755-761（2021）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Zheng, S. Q. et al. MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat. Methods 14, 331–332 (2017).Article

Zheng，S.Q.等人。MotionCor2：改进低温电子显微镜的束流诱导运动的各向异性校正。自然方法14331-332（2017）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Rohou, A. & Grigorieff, N. CTFFIND4: fast and accurate defocus estimation from electron micrographs. J. Struct. Biol. 192, 216–221 (2015).Article

Rohou，A。＆Grigorieff，N。CTFFIND4：从电子显微照片快速准确地估计散焦。J、结构。生物学192216-221（2015）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Sanchez-Garcia, R. et al. DeepEMhancer: a deep learning solution for cryo-EM volume post-processing. Commun. Biol. 4, 874 (2021).Article

Sanchez-Garcia，R.等人，《DeepEMhancer：低温电磁体积后处理的深度学习解决方案》。Commun公司。生物学4874（2021）。文章

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).Article

Jumper，J.等人。使用AlphaFold进行高度准确的蛋白质结构预测。自然596583-589（2021）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Pettersen, E. F. et al. UCSF Chimera-a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).Article

Pettersen，E.F.等人，《UCSF Chimera——探索性研究和分析的可视化系统》。J、计算机。。251605-1612（2004）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. Sect. D Biol. Crystallogr. 66, 486–501 (2010).Article

Emsley，P.，Lohkamp，B.，Scott，W.G。和Cowtan，K。Coot的特征和发展。晶体学报。第节。D生物晶体学。66486-501（2010）。文章

CAS

中科院

Google Scholar

谷歌学者

Liebschner, D. et al. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr. Sect. D Struct. Biol. 75, 861–877 (2019).Article

Liebschner，D.等人，《利用X射线、中子和电子测定大分子结构：Phenix的最新进展》。晶体学报。第节。D结构。生物学75861-877（2019）。文章

CAS

中科院

Google Scholar

谷歌学者

Pettersen, E. F. et al. UCSF ChimeraX: structure visualization for researchers, educators, and developers. Protein Sci. 30, 70–82 (2021).Article

Pettersen，E.F.等人，《UCSF ChimeraX：研究人员、教育者和开发人员的结构可视化》。蛋白质科学。30，70-82（2021）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Olsen, R. H. J. et al. TRUPATH, an open-source biosensor platform for interrogating the GPCR transducerome. Nat. Chem. Biol. 16, 841–849 (2020).Article

Olsen，R.H.J.等人，TRUPATH，一种用于询问GPCR转导组的开源生物传感器平台。自然化学。生物学16841-849（2020）。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Olsson, M. H., Søndergaard, C. R., Rostkowski, M. & Jensen, J. H. PROPKA3: consistent treatment of internal and surface residues in empirical pKa predictions. J. Chem. Theory Comput. 7, 525–537 (2011).Article

Olsson，M.H.，Søndergaard，C.R.，Rostkowski，M。＆Jensen，J.H。PROPKA3：在经验pKa预测中对内部和表面残留物的一致处理。J、化学。理论计算。7525-537（2011）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Wu, E. L. et al. CHARMM-GUI Membrane Builder toward realistic biological membrane simulations. J. Comput. Chem. 35, 1997–2004 (2014).Article

Wu，E.L.等人。CHARMM-GUI膜构建器面向现实的生物膜模拟。J、计算机。。。文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Huang, J. et al. CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nat. Methods 14, 71–73 (2017).Article

Huang，J。等人。CHARMM36m：折叠和本质无序蛋白质的改进力场。自然方法14,71-73（2017）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Salomon-Ferrer, R., Götz, A. W., Poole, D., Le Grand, S. & Walker, R. C. Routine microsecond molecular dynamics simulations with AMBER on GPUs. 2. Explicit solvent particle mesh Ewald. J. Chem. Theory Comput. 9, 3878–3888 (2013).Article

Salomon Ferrer，R.，Götz，A.W.，Poole，D.，Le Grand，S。＆Walker，R.C。在GPU上使用AMBER进行常规微秒分子动力学模拟。2.显式溶剂颗粒网格Ewald。J、化学。理论计算。93878-3888（2013）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Miller, B. R. 3rd et al. MMPBSA.py: an efficient program for end-state free energy calculations. J. Chem. Theory Comput. 8, 3314–3321 (2012).Article

Miller，B.R.3rd等人，《MMPBSA.py：一种有效的末端自由能计算程序》。J、化学。理论计算。83314-3321（2012）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Roe, D. R. & Cheatham, T. E. III PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data. J. Chem. Theory Comput. 9, 3084–3095 (2013).Article

Roe，D。R。＆Cheatham，T。E。III PTRAJ和CPPTRAJ：用于处理和分析分子动力学轨迹数据的软件。J、化学。理论计算。93084-3095（2013）。文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Download referencesAcknowledgementsThe cryo-EM data were collected at Advanced Center for Electron Microscopy at Shanghai Institute of Materia Medica, Chinese Academy of Sciences. We are grateful to Kai Wu and Wen Hu for collecting the cryo-EM data. We thank Zecai Chen, Xue Meng, and Jiuyin Xu for helping with experiments.

下载参考文献致谢低温电磁数据是在中国科学院上海药物研究所高级电子显微镜中心收集的。我们感谢吴凯和胡文收集了低温电磁数据。我们感谢Zecai Chen，Xue Meng和Jiuyin Xu对实验的帮助。

This work was supported by the National Key R&D Program of China (2022YFC2703105 to H.E.X., 2019YFA0904200); the National Natural Science Foundation of China (32371255 and 32071203 to L.-H.Z., 32130022 and 82121005 to H.E.X.); the Natural Science Foundation of Shanghai (23ZR1475200 to L.-H.Z.); CAS Strategic Priority Research Program (XDB37030103 to H.E.X.); Shanghai Municipal Science and Technology Major Project (2019SHZDZX02 to H.E.X.); the Young Innovator Association of CAS (Y2022078 to L.-H.Z.); the Lingang Laboratory (LG-GG-202204-01 to H.E.X.); State Key Laboratory of Drug Research (SKLDR-2023-TT-04 to H.E.X.).Author informationAuthor notesThese authors contributed equally: Yang Li, Qingning Yuan.Authors and AffiliationsState Key Laboratory of Drug Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaYang Li, Xinheng He, Yumu Zhang, Chongzhao You, Canrong Wu, Jingru Li, H.

这项工作得到了中国国家重点研发计划（2022YFC2703105 to H.E.X.，2019YFA0904200）的支持；国家自然科学基金（L.H.Z.32371255和32071203，H.E.X.32130022和82121005）；上海自然科学基金（23ZR1475200至L.-H.Z.）；中科院战略优先研究计划（XDB37030103至H.E.X.）；上海市科技重大项目（2019SHZDZX02至H.E.X.）；中国科学院青年创新者协会（Y2022078至L.-H.Z.）；临港实验室（LG-GG-202204-01至H.E.X.）；药物研究国家重点实验室（SKLDR-2023-TT-04至H.E.X.）。作者信息作者注意到这些作者做出了同样的贡献：杨莉，袁庆宁。作者和单位中国科学院上海药物研究所药物靶标结构与功能中心药物研究国家重点实验室，中国上海杨莉，何信恒，张玉木，尤崇昭，吴灿荣，李景如，H。

Eric Xu & Li-Hua ZhaoUniversity of Chinese Academy of Sciences, Beijing, ChinaYang Li, Xinheng He, Chongzhao You, H. Eric Xu & Li-Hua ZhaoSchool of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, ChinaQingning Yuan & Jingru LiTranslational Center for Medicinal Structural Biology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaLi-Hua ZhaoAuthorsYang LiView author publicationsYou can also search for this au.

埃里克·徐和李华昭中国科学院大学，北京，李阳，何信恒，尤崇昭，H。南京中医药大学中药学院Eric Xu＆Li Hua Zhao，南京中医药大学，南京，江苏，中国上海，上海交通大学医学院瑞金医院药物结构生物学翻译中心，中国上海Li Hua Zhao作者Yang LiView作者出版物你也可以搜索这个au。

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PubMed Google ScholarContributionsY.L. designed the expression constructs and purified the protein complex under supervision of L.-H.Z. and H.E.X.; L.-H.Z. prepared the grids. Q.Y. performed cryo-EM data processing and model building. X.H. performed MD simulation. Y.L. constructed all the mutated plasmids and performed functional studies under supervision of L.-H.Z.

PubMed谷歌学术贡献。五十、在L.-H.Z.和H.E.X.的监督下设计表达构建体并纯化蛋白质复合物。；五十、 -H.Z.准备网格。Q、 Y.进行了低温电磁数据处理和模型构建。十、。Y、 L.构建了所有突变质粒，并在L.-H.Z.的监督下进行了功能研究。

and Y.Z.; J.L. helped with functional experiments. Y.L., C.Y. and Y.Z. participated in analyzing the structures. Y.L. prepared the figures and initial manuscript. C.Y. and Y.Z. participated in the preparation of the figures. C.W. participated in manuscript preparation. All authors discussed and commented on the manuscript.

和Y.Z。；J、 L.帮助进行功能实验。Y、 L.，C.Y.和Y.Z.参与了结构分析。Y、 L.准备了数字和初稿。C、 Y.和Y.Z.参与了数字的编制。C、 W.参与了稿件准备。所有作者都对稿件进行了讨论和评论。

L.-H.Z. and H.E.X. revised the manuscript. L.-H.Z and H.E.X. conceived, designed, and supervised the overall project.Corresponding authorsCorrespondence to.

五十、 -H.Z.和H.E.X.修改了手稿。五十、 -H.Z和H.E.X.构思、设计并监督了整个项目。通讯作者通讯。

H. Eric Xu or Li-Hua Zhao.Ethics declarations

H、 Eric Xu或Li Hua Zhao。道德宣言

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Reprints and permissionsAbout this articleCite this articleLi, Y., Yuan, Q., He, X. et al. Molecular mechanism of prolactin-releasing peptide recognition and signaling via its G protein-coupled receptor.

转载和许可本文引用本文Li，Y.，Yuan，Q.，He，X。等人。催乳素释放肽识别的分子机制和通过其G蛋白偶联受体的信号传导。

Cell Discov 10, 91 (2024). https://doi.org/10.1038/s41421-024-00724-6Download citationReceived: 25 January 2024Accepted: 06 August 2024Published: 03 September 2024DOI: https://doi.org/10.1038/s41421-024-00724-6Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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