A method for structure determination of GPCRs in various states

Guo, Qiong; He, Binbin; Zhong, Yanfei; Jiao, Haizhan; Ren, Yinhang; Wang, Qinggong; Ge, Qiangqiang; Gao, Yongxiang; Liu, Xiangyu; Du, Yang; Hu, Hongli; Tao, Yuyong

doi:10.1038/s41589-023-01389-0

Cited by 16 publications

(11 citation statements)

References 59 publications

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“…To understand the antagonism of MCHR1, we tried to solve the structure of the inactive-state MCHR1 bound to a selective antagonist SNAP-94847. To this end, we applied a previously described strategy 38 to determine this structure by cryo-EM. We engineered the human MCHR1 by inserting mBRIL between TM5 and TM6 to replace the ICL3 in a rigid fashion and fused a K3 helix together with an ALFA tag to H8 of MCHR1.…”

Section: Resultsmentioning

confidence: 99%

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Structural insights into physiological activation and antagonism of melanin-concentrating hormone receptor MCHR1

Ye,

Liu,

et al. 2024

Preprint

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Melanin-concentrating hormone (MCH) is a 19-amino-acid neuropeptide playing crucial roles in energy homeostasis, sleep, and various physiological processes. It acts through two G protein-coupled receptors, MCHR1 and MCHR2, with MCHR1 being universally present in mammals and a potential target for treating metabolic and mental health conditions. However, drug development efforts have been impeded by the lack of structural information. Here, we present the cryo-EM structures of MCHR1 in its active state complexed with MCH and Gi1, as well as in its inactive state bound to a selective antagonist SNAP-94847. Structural and mutagenesis analyses disclosed the recognition mechanisms for both MCH and SNAP-94847, the activation mechanism and antagonism of MCHR1, and the determinants of ligand specificity. These findings are expected to accelerate the development of better drugs targeting the MCH system.

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Section: Resultsmentioning

confidence: 99%

“…For structure determination of the antagonist-bond MCHR1, a previously described strategy was applied 38 . To fuse mBRIL to MCHR1 in a rigid fashion, the active-state structure of MCHR1 was aligned with the previous β 2 AR-mBRIL construct.…”

Section: Methodsmentioning

confidence: 99%

Structural insights into physiological activation and antagonism of melanin-concentrating hormone receptor MCHR1

Ye,

Liu,

et al. 2024

Preprint

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“…A characteristic feature of the ET B -CN-FKBP12 complex is the acquired interaction between ET B and calcineurin. In general, receptors and fusion partners are inherently non-interacting combinations and do not interact outside of the fusion point 23, 24 (Extended Data Fig. 4a).…”

Section: Resultsmentioning

confidence: 99%

Structure of a lasso peptide bound ETB receptor provides insights into the mechanism of GPCR inverse agonism

Shihoya,

Akasaka,

Jordan

et al. 2024

Preprint

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Lasso peptides exhibit a unique lariat-like knotted structure imparting exceptional stability and thus show promise as therapeutic agents that target cell-surface receptors. One such receptor is the human endothelin ETB receptor, which is implicated in challenging cancers with poor immunotherapy responsiveness. The Streptomyces-derived lasso peptide, RES-701-3, is a selective inhibitor for ETB and a compelling candidate for therapeutic development. However, meager production from a genetically recalcitrant host has limited further structure-activity relationship studies of this potent inhibitor. Here, we report cryo-electron microscopy structures of ETB receptor in both its apo form and complex with RES-701-3, facilitated by a calcineurin-fusion strategy. Hydrophobic interactions between RES-701-3 and the transmembrane region of the receptor, especially involving two tryptophan residues, play a crucial role in RES-701-3 binding. Furthermore, RES-701-3 prevents conformational changes associated with G-protein coupling, explaining its inverse agonist activity. A comparative analysis with other lasso peptides and their target proteins highlights the potential of lasso peptides as precise drug candidates for G-protein-coupled receptors. This structural insight into RES-701-3 binding to ETB receptor offers valuable information for the development of novel therapeutics targeting this receptor and provides a broader understanding of lasso peptide interactions with human cell-surface receptors.

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“…Current MT 1 and MT 2 structures were obtained in the presence of nonselective agonists only. The XFEL method and recent advances of cryo‐EM methods are likely to enable the acquisition of subtype‐selective and antagonist binding modes, 23,105 which is expected to improve the outcomes of structure‐based drug design. Additionally, the combination of complementary experimental techniques (e.g., crystallography, NMR, and spectroscopy) and computational simulations will help to clarify aspects of MTRs still poorly appreciated, as the identification of allosteric sites, the driving elements for biased signaling and the mechanism of receptor dimerization and oligomerization.…”

Section: Perspectivesmentioning

confidence: 99%

Melatonin receptor structure and signaling

Okamoto,

Cecon,

Nureki

et al. 2024

Journal of Pineal Research

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Melatonin (5‐methoxy‐N‐acetyltryptamine) binds with high affinity and specificity to membrane receptors. Several receptor subtypes exist in different species, of which the mammalian MT1 and MT2 receptors are the best‐characterized. They are members of the G protein‐coupled receptor superfamily, preferentially coupling to Gi/o proteins but also to other G proteins in a cell‐context‐depending manner. In this review, experts on melatonin receptors will summarize the current state of the field. We briefly report on the discovery and classification of melatonin receptors, then focus on the molecular structure of human MT1 and MT2 receptors and highlight the importance of molecular simulations to identify new ligands and to understand the structural dynamics of these receptors. We then describe the state‐of‐the‐art of the intracellular signaling pathways activated by melatonin receptors and their complexes. Brief statements on the molecular toolbox available for melatonin receptor studies and future perspectives will round‐up this review.

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A method for structure determination of GPCRs in various states

Cited by 16 publications

References 59 publications

Structural insights into physiological activation and antagonism of melanin-concentrating hormone receptor MCHR1

Structural insights into physiological activation and antagonism of melanin-concentrating hormone receptor MCHR1

Structure of a lasso peptide bound ETB receptor provides insights into the mechanism of GPCR inverse agonism

Melatonin receptor structure and signaling

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