结构基础：B 类 G 蛋白偶联受体的别构调节。
Structural Basis for Allosteric Modulation of Class B G Protein-Coupled Receptors.
机构信息
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, and Department of Pharmacology, Monash University, Parkville 3052, Australia; email:
School of Pharmacy, Fudan University, Shanghai 201203, China.
出版信息
Annu Rev Pharmacol Toxicol. 2020 Jan 6;60:89-107. doi: 10.1146/annurev-pharmtox-010919-023301. Epub 2019 Aug 27.
Abstract
Recent advances in our understanding of the structure and function of class B G protein-coupled receptors (GPCRs) provide multiple opportunities for targeted development of allosteric modulators. Given the pleiotropic signaling patterns emanating from these receptors in response to a variety of natural agonist ligands, modulators have the potential to sculpt the responses to meet distinct needs of different groups of patients. In this review, we provide insights into how this family of GPCRs differs from the rest of the superfamily, how orthosteric agonists bind and activate these receptors, the potential for allosteric modulators to interact with various regions of these targets, and the allosteric influence of endogenous proteins on the pharmacology of these receptors, all of which are important considerations when developing new therapies.
摘要
近年来，我们对 B 类 G 蛋白偶联受体（GPCR）的结构和功能的理解取得了进展，为变构调节剂的靶向开发提供了多种机会。鉴于这些受体对各种天然激动剂配体的反应产生的多效性信号模式，调节剂有可能塑造反应，以满足不同患者群体的不同需求。在这篇综述中，我们深入了解了这个 GPCR 家族与超家族的其他成员有何不同，变构激动剂如何结合并激活这些受体，变构调节剂与这些靶标的不同区域相互作用的潜力，以及内源性蛋白对这些受体药理学的变构影响，所有这些都是开发新疗法时需要考虑的重要因素。
相似文献
1
Structural Basis for Allosteric Modulation of Class B G Protein-Coupled Receptors.结构基础：B 类 G 蛋白偶联受体的别构调节。
Annu Rev Pharmacol Toxicol. 2020 Jan 6;60:89-107. doi: 10.1146/annurev-pharmtox-010919-023301. Epub 2019 Aug 27.
2
Allosteric Modulators of the Class A G Protein Coupled Receptors.A类G蛋白偶联受体的变构调节剂
Adv Exp Med Biol. 2016;917:185-207. doi: 10.1007/978-3-319-32805-8_9.
3
Strategies for the identification of allosteric modulators of G-protein-coupled receptors.G 蛋白偶联受体变构调节剂的鉴定策略。
Biochem Pharmacol. 2011 Mar 15;81(6):691-702. doi: 10.1016/j.bcp.2010.12.012. Epub 2010 Dec 22.
4
Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators.游离脂肪酸受体及其别构调节剂的药理学。
Int J Mol Sci. 2021 Feb 10;22(4):1763. doi: 10.3390/ijms22041763.
5
Allosteric modulation of family C G-protein-coupled receptors: from molecular insights to therapeutic perspectives.家族 C G 蛋白偶联受体的别构调节：从分子见解到治疗视角。
Pharmacol Rev. 2011 Mar;63(1):59-126. doi: 10.1124/pr.109.002501. Epub 2011 Jan 12.
6
Allosteric modulation of G-protein coupled receptors.G蛋白偶联受体的变构调节
Eur J Pharm Sci. 2004 Mar;21(4):407-20. doi: 10.1016/j.ejps.2003.11.007.
7
Allosteric modulators of rhodopsin-like G protein-coupled receptors: opportunities in drug development.视紫红质样 G 蛋白偶联受体的变构调节剂：药物开发的机遇。
Pharmacol Ther. 2012 Sep;135(3):292-315. doi: 10.1016/j.pharmthera.2012.06.002. Epub 2012 Jun 19.
8
Molecular insights into allosteric modulation of Class C G protein-coupled receptors.对C类G蛋白偶联受体变构调节的分子见解。
Pharmacol Res. 2017 Feb;116:105-118. doi: 10.1016/j.phrs.2016.12.006. Epub 2016 Dec 11.
9
Recent Advances in the Drug Discovery and Development of Dualsteric/ Bitopic Activators of G Protein-Coupled Receptors.双功能/双位点 G 蛋白偶联受体激动剂的药物发现和开发的最新进展。
Curr Top Med Chem. 2019;19(26):2378-2392. doi: 10.2174/1568026619666191009164609.
10
High-Throughput Screening for Allosteric Modulators of GPCRs.G蛋白偶联受体变构调节剂的高通量筛选
Methods Mol Biol. 2015;1335:223-40. doi: 10.1007/978-1-4939-2914-6_15.
引用本文的文献
1
G protein-coupled receptors: pivotal hubs in gastric cancer malignancy-from multidimensional crosstalk to precision therapeutics.G蛋白偶联受体：胃癌恶性肿瘤中的关键枢纽——从多维串扰到精准治疗
J Transl Med. 2025 Aug 7;23(1):879. doi: 10.1186/s12967-025-06851-2.
2
Insights into the structural dynamics of the secretin family (class B1) G protein-coupled receptors.促胰液素家族（B1类）G蛋白偶联受体的结构动力学研究进展。
J Biol Chem. 2025 Jul 9;301(8):110466. doi: 10.1016/j.jbc.2025.110466.
3
Allosteric communication mechanism in the glucagon receptor.胰高血糖素受体中的变构通讯机制。
J Biol Chem. 2025 Apr 23;301(6):108530. doi: 10.1016/j.jbc.2025.108530.
4
LYCHOS is a human hybrid of a plant-like PIN transporter and a GPCR.LYCHOS 是一种植物样 PIN 转运蛋白和 GPCR 的人源杂合体。
Nature. 2024 Oct;634(8036):1238-1244. doi: 10.1038/s41586-024-08012-9. Epub 2024 Oct 2.
5
Lipid regulation of the glucagon receptor family.胰高血糖素受体家族的脂质调节。
J Endocrinol. 2024 May 6;261(3). doi: 10.1530/JOE-23-0335. Print 2024 Jun 1.
6
Targeting VIP and PACAP Receptor Signaling: New Insights into Designing Drugs for the PACAP Subfamily of Receptors.靶向 VIP 和 PACAP 受体信号：设计 PACAP 受体亚家族药物的新见解。
Int J Mol Sci. 2022 Jul 22;23(15):8069. doi: 10.3390/ijms23158069.
7
The Nonpeptide Agonist MK-5046 Functions As an Allosteric Agonist for the Bombesin Receptor Subtype-3.非肽类激动剂 MK-5046 作为蛙皮素受体亚型-3 的变构激动剂发挥作用。
J Pharmacol Exp Ther. 2022 Aug;382(2):66-78. doi: 10.1124/jpet.121.001033. Epub 2022 May 29.
8
The metabolite GLP-1 (9-36) is neuroprotective and anti-inflammatory in cellular models of neurodegeneration.GLP-1（9-36）代谢物在神经退行性变的细胞模型中具有神经保护和抗炎作用。
J Neurochem. 2021 Dec;159(5):867-886. doi: 10.1111/jnc.15521. Epub 2021 Oct 21.
9
Molecular insights into differentiated ligand recognition of the human parathyroid hormone receptor 2.人甲状旁腺激素受体 2 对分化配体识别的分子见解。
Proc Natl Acad Sci U S A. 2021 Aug 10;118(32). doi: 10.1073/pnas.2101279118.
10
Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening.基于结构和配体的虚拟筛选发现靶向 GLP-1R 额外螺旋结合位点的新型别构调节剂。
Biomolecules. 2021 Jun 23;11(7):929. doi: 10.3390/biom11070929.
本文引用的文献
1
Shaky ground - The nature of metastable GPCR signalling complexes.摇摇欲坠的基础——不稳定 G 蛋白偶联受体信号复合物的本质。
Neuropharmacology. 2019 Jul 1;152:4-14. doi: 10.1016/j.neuropharm.2019.01.018. Epub 2019 Jan 17.
2
High-resolution crystal structure of parathyroid hormone 1 receptor in complex with a peptide agonist.甲状旁腺激素 1 受体与肽激动剂复合物的高分辨率晶体结构。
Nat Struct Mol Biol. 2018 Dec;25(12):1086-1092. doi: 10.1038/s41594-018-0151-4. Epub 2018 Nov 19.
3
Cryo-EM structure of the active, G-protein complexed, human CGRP receptor.活性态、与 G 蛋白复合物结合的人降钙素基因相关肽受体的冷冻电镜结构。
Nature. 2018 Sep;561(7724):492-497. doi: 10.1038/s41586-018-0535-y. Epub 2018 Sep 12.
4
Differential engagement of polar networks in the glucagon-like peptide 1 receptor by endogenous variants of the glucagon-like peptide 1.胰高血糖素样肽 1 内源性变体对胰高血糖素样肽 1 受体的极性网络的差异化结合
Biochem Pharmacol. 2018 Oct;156:223-240. doi: 10.1016/j.bcp.2018.08.033. Epub 2018 Aug 25.
5
Structural insights into G-protein-coupled receptor allostery.G 蛋白偶联受体变构的结构见解。
Nature. 2018 Jul;559(7712):45-53. doi: 10.1038/s41586-018-0259-z. Epub 2018 Jul 4.
6
FDA approves licensing of erenumab-aooe to prevent migraine.美国食品药品监督管理局批准erenumab-aooe的许可用于预防偏头痛。
Am J Health Syst Pharm. 2018 Jul 1;75(13):929-930. doi: 10.2146/news180044.
7
CGRP and Migraine: The Role of Blocking Calcitonin Gene-Related Peptide Ligand and Receptor in the Management of Migraine.降钙素基因相关肽与偏头痛：阻断降钙素基因相关肽配体和受体在偏头痛治疗中的作用。
Drugs. 2018 Jun;78(9):913-928. doi: 10.1007/s40265-018-0923-5.
8
Two distinct domains of the glucagon-like peptide-1 receptor control peptide-mediated biased agonism.胰高血糖素样肽-1 受体的两个不同结构域控制肽介导的偏性激动作用。
J Biol Chem. 2018 Jun 15;293(24):9370-9387. doi: 10.1074/jbc.RA118.003278. Epub 2018 May 1.
9
CGRP as the target of new migraine therapies - successful translation from bench to clinic.降钙素基因相关肽（CGRP）作为新型偏头痛治疗靶点——从实验室到临床的成功转化。
Nat Rev Neurol. 2018 Jun;14(6):338-350. doi: 10.1038/s41582-018-0003-1.
10
Chemical Diversity in the G Protein-Coupled Receptor Superfamily.G 蛋白偶联受体超家族的化学多样性。
Trends Pharmacol Sci. 2018 May;39(5):494-512. doi: 10.1016/j.tips.2018.02.004. Epub 2018 Mar 22.
Zotero 插件