The relaxin receptor RXFP1 signals through a mechanism of autoinhibition

Erlandson, Sarah C.; Rawson, Shaun; Osei-Owusu, James; Brock, Kelly; Paulo, João A.; Mintseris, Julian; Gygi, Steven P.; Marks, Debora S.; Cong, Xiaojing; Kruse, Andrew C.

doi:10.1038/s41589-023-01321-6

Cited by 12 publications

(6 citation statements)

References 58 publications

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“…They all contain an A- and B-chain fused by two interchain disulfide bonds and one intrachain disulfide bond in the A-chain. The biophysical and molecular mechanisms by which relaxin H2 binds to and activates RXFP1 are partly understood and subject to active research by several groups. − There is consensus that relaxin first binds to the leucine rich repeats (LRR) motif in the RXFP1 ectodomain, which in turn elicits the concerted action of multiple receptor domains leading to RXFP1 activation and signal transduction. A notable structural feature of RXFP1 is its NH 2 -terminal low-density lipoprotein receptor type A (LDLa) module, which plays a vital role in relaxin-mediated receptor activation and is unique for RXFP1 and 2 across the GPCRome …”

Section: Introductionmentioning

confidence: 99%

Identification of Novel Series of Potent and Selective Relaxin Family Peptide Receptor 1 (RXFP1) Agonists

Granberg,

Sakamaki,

Fuchigami

et al. 2024

J. Med. Chem.

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Relaxin H2 is a clinically relevant peptide agonist for relaxin family peptide receptor 1 (RXFP1), but a combination of this hormone's short plasma half-life and the need for injectable delivery limits its therapeutic potential. We sought to overcome these limitations through the development of a potent small molecule (SM) RXFP1 agonist. Although two large SM HTS campaigns failed in identifying suitable hit series, we uncovered novel chemical space starting from the only known SM RXFP1 agonist series, represented by ML290. Following a design−make− test−analyze strategy based on improving early dose to man ranking, we discovered compound 42 (AZ7976), a highly selective RXFP1 agonist with sub-nanomolar potency. We used AZ7976, its 10 000-fold less potent enantiomer 43 and recombinant relaxin H2 to evaluate in vivo pharmacology and demonstrate that AZ7976-mediated heart rate increase in rats was a result of RXFP1 agonism. As a result, AZ7976 was selected as lead for continued optimization.

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Section: Introductionmentioning

confidence: 99%

Identification of Novel Series of Potent and Selective Relaxin Family Peptide Receptor 1 (RXFP1) Agonists

Granberg,

Sakamaki,

Fuchigami

et al. 2024

J. Med. Chem.

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“…RXFP1 serves as a receptor for relaxins, with its activity facilitated through G proteins. This interaction stimulates adenylate cyclase, leading to elevated cAMP levels [ 83 ]. The expression of RXFP1 is directly related to the pulmonary function of patients with Idiopathic Pulmonary Fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Evolutionary genetics of pulmonary anatomical adaptations in deep-diving cetaceans

Guo,

Sun,

Wang

et al. 2024

BMC Genomics

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Background Cetaceans, having experienced prolonged adaptation to aquatic environments, have undergone evolutionary changes in their respiratory systems. This process of evolution has resulted in the emergence of distinctive phenotypic traits, notably the abundance of elastic fibers and thickened alveolar walls in their lungs, which may facilitate alveolar collapse during diving. This structure helps selective exchange of oxygen and carbon dioxide, while minimizing nitrogen exchange, thereby reducing the risk of DCS. Nevertheless, the scientific inquiry into the mechanisms through which these unique phenotypic characteristics govern the diving behavior of marine mammals, including cetaceans, remains unresolved. Results This study entails an evolutionary analysis of 42 genes associated with pulmonary fibrosis across 45 mammalian species. Twenty-one genes in cetaceans exhibited accelerated evolution, featuring specific amino acid substitutions in 14 of them. Primarily linked to the development of the respiratory system and lung morphological construction, these genes play a crucial role. Moreover, among marine mammals, we identified eight genes undergoing positive selection, and the evolutionary rates of three genes significantly correlated with diving depth. Specifically, the SFTPC gene exhibited convergent amino acid substitutions. Through in vitro cellular experiments, we illustrated that convergent amino acid site mutations in SFTPC contribute positively to pulmonary fibrosis in marine mammals, and the presence of this phenotype can induce deep alveolar collapse during diving, thereby reducing the risk of DCS during diving. Conclusions The study unveils pivotal genetic signals in cetaceans and other marine mammals, arising through evolution. These genetic signals may influence lung characteristics in marine mammals and have been linked to a reduced risk of developing DCS. Moreover, the research serves as a valuable reference for delving deeper into human diving physiology.

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“…Furthermore, the cryo-electron microscopy structure of active-state human RXFP1, bound to a single-chain version of the endogenous agonist RLN and the heterotrimeric Gs protein, has been elucidated. This study uncovers that RXFP1 signals through a mechanism of autoinhibition, adding a new layer of complexity to understanding of these receptors [ 149 ]. Understanding this interaction mechanism provides crucial information for the development of drugs targeting RXFPs.…”

Section: Discussionmentioning

confidence: 99%

The diverse influences of relaxin-like peptide family on tumor progression: Potential opportunities and emerging challenges

Jung,

Han

2024

Heliyon

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The relaxin receptor RXFP1 signals through a mechanism of autoinhibition

Cited by 12 publications

References 58 publications

Identification of Novel Series of Potent and Selective Relaxin Family Peptide Receptor 1 (RXFP1) Agonists

Identification of Novel Series of Potent and Selective Relaxin Family Peptide Receptor 1 (RXFP1) Agonists

Evolutionary genetics of pulmonary anatomical adaptations in deep-diving cetaceans

The diverse influences of relaxin-like peptide family on tumor progression: Potential opportunities and emerging challenges

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