ArticleBiochemistry2016
Structural Insights into the Activation of Human Relaxin Family Peptide Receptor 1 by Small-Molecule Agonists.
Article in Biochemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 28 citations in OpenAlex.
- Long-acting relaxin analogues: a novel tool in cardiology.Frontiers in pharmacology · 2025Review
- The relaxin receptor RXFP1 signals through a mechanism of autoinhibition.Nature chemical biology · 2023Article
- Discovery of small molecule agonists of the Relaxin Family Peptide Receptor 2.Communications biology · 2022Article
- Synaptamide activates the adhesion GPCR GPR110 (ADGRF1) through GAIN domain binding.Communications biology · 2020Article
- Therapeutic effects of a small molecule agonist of the relaxin receptor ML290 in liver fibrosis.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
- Understanding Peptide Binding in Class A G Protein-Coupled Receptors.Molecular pharmacology · 2019Review
- Targeting the relaxin/insulin-like family peptide receptor 1 and 2 with small molecule compounds.Molecular and cellular endocrinology · 2019Review
- Optimization of the first small-molecule relaxin/insulin-like family peptide receptor (RXFP1) agonists: Activation results in an antifibrotic gene expression profile.European journal of medicinal chemistry · 2018Article
- Heart Disease and Relaxin: New Actions for an Old Hormone.Trends in endocrinology and metabolism: TEM · 2018Review
- Distinct activation modes of the Relaxin Family Peptide Receptor 2 in response to insulin-like peptide 3 and relaxin.Scientific reports · 2017Article
- ML290 is a biased allosteric agonist at the relaxin receptor RXFP1.Scientific reports · 2017Article
- Human Relaxin Receptor Is Fully Functional in Humanized Mice and Is Activated by Small Molecule Agonist ML290.Journal of the Endocrine Society · 2017Article
- Relaxin-like peptides in male reproduction - a human perspective.British journal of pharmacology · 2017Review
- Synthetic non-peptide low molecular weight agonists of the relaxin receptor 1.British journal of pharmacology · 2017Review
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
The GPCR relaxin family peptide receptor 1 (RXFP1) mediates the action of relaxin peptide hormone, including its tissue remodeling and antifibrotic effects. The peptide has a short half-life in plasma, limiting its therapeutic utility. However, small-molecule agonists of human RXFP1 can overcome this limitation and may provide a useful therapeutic approach, especially for chronic diseases such as heart failure and fibrosis. The first small-molecule agonists of RXFP1 were recently identified from a high-throughput screening, using a homogeneous cell-based cAMP assay. Optimization of the hit compounds resulted in a series of highly potent and RXFP1 selective agonists with low cytotoxicity, and excellent in vitro ADME and pharmacokinetic properties. Here, we undertook extensive site-directed mutagenesis studies in combination with computational modeling analysis to probe the molecular basis of the small-molecule binding to RXFP1. The results showed that the agonists bind to an allosteric site of RXFP1 in a manner that closely interacts with the seventh transmembrane domain (TM7) and the third extracellular loop (ECL3). Several residues were determined to play an important role in the agonist binding and receptor activation, including a hydrophobic region at TM7 consisting of W664, F668, and L670. The G659/T660 motif within ECL3 is crucial to the observed species selectivity of the agonists for RXFP1. The receptor binding and activation effects by the small molecule ML290 were compared with the cognate ligand, relaxin, providing valuable insights on the structural basis and molecular mechanism of receptor activation and selectivity for RXFP1.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.