Structural basis for the constitutive activity of the melanocortin receptor family

IF 4.3 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Structure Pub Date : 2025-03-28 DOI:10.1016/j.str.2025.03.004

Wenbo Feng, Qingtong Zhou, Chang Zheng, Dehua Yang, Ming-Wei Wang

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Abstract

The constitutive activity of melanocortin receptors (MCRs) is integral to several physiological processes. The unliganded cryo-electron microscopy structures of MC1R, MC2R, MC3R, MC4R, and MC5R in complex with G_s proteins determined at global resolutions of 2.98 Å, 3.01 Å, 2.75 Å, 3.12 Å, and 2.86 Å, respectively, revealed that their binding poses and interactions with G_s are similar to those of agonist-bound MCRs. The extracellular regions of the transmembrane helices (TMs) exhibit distinct conformational rearrangements, characterized by varying shifts of TM3 and outward displacements of TM4. These variations represent unique structural features of constitutively activated MCRs. Unassigned electron densities were observed within the orthosteric pockets where extensive interactions with cognate ligands occur. In addition, zinc ions, but not calcium, positively regulated MC4R activity in a dose-dependent manner. Our findings provide valuable insights into the molecular mechanisms underlying MCR basal activity and highlight the role of divalent ions in receptor activation.

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黑素皮质素受体家族组成活性的结构基础

黑素皮质素受体（mcr）的组成活性是不可或缺的几个生理过程。MC1R、MC2R、MC3R、MC4R和MC5R与Gs蛋白复合物的无配体低温电镜结构（全局分辨率分别为2.98 Å、3.01 Å、2.75 Å、3.12 Å和2.86 Å）显示，它们的结合姿态和与Gs的相互作用与激动剂结合的mcr相似。跨膜螺旋（tmms）的胞外区域表现出明显的构象重排，其特征是TM3的移位和TM4的向外移位。这些变异代表了本构激活mcr的独特结构特征。在与同源配体发生广泛相互作用的正构口袋中观察到未分配的电子密度。此外，锌离子，而不是钙离子，以剂量依赖的方式正向调节MC4R活性。我们的发现为MCR基础活性的分子机制提供了有价值的见解，并强调了二价离子在受体激活中的作用。

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来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.