ArticleFASEB bioAdvances2024
Osteocalcin binds to a GPRC6A Venus fly trap allosteric site to positively modulate GPRC6A signaling.
Article in FASEB bioAdvances, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
What it found
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Who cites it
4 citing papers in PubMed.
- Osteocalcin Beyond Bone: Molecular Mechanisms, Endocrine Networks, and Translational Perspectives Across Metabolism, Neurobiology, and Chronic Disease.International journal of molecular sciences · 2026Review
- Activating the Osteoblastic USP26 Pathway Alleviates Multi-Organ Fibrosis by Decreasing Insulin Resistance.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Osteocalcin binds to a GPRC6A Venus fly trap allosteric site to positively modulate GPRC6A signaling.FASEB bioAdvances · 2024Article
- GPRC6A is a Potential Therapeutic Target for Metformin Regulation of Glucose Homeostasis in Mice.bioRxiv : the preprint server for biology · 2024Article
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Authors and funding
6 authors.
Funding
Abstract
GPRC6A, a member of the Family C G-protein coupled receptors, regulates energy metabolism and sex hormone production and is activated by diverse ligands, including cations, L-amino acids, the osteocalcin (Ocn) peptide and the steroid hormone testosterone. We sought a structural framework for the ability of multiple distinct classes of ligands to active GPRC6A. We created a structural model of GPRC6A using Alphafold2. Using this model we explored a putative orthosteric ligand binding site in the bilobed Venus fly trap (VFT) domain of GPRC6A and two positive allosteric modulator (PAM) sites, one in the VFT and the other in the 7 transmembrane (7TM) domain. We provide evidence that Ocn peptides act as a PAM for GPRC6A by binding to a site in the VFT that is distinct from the orthosteric site for calcium and L-amino acids. In agreement with this prediction, alternatively spliced GPRC6A isoforms 2 and 3, which lack regions of the VFT, and mutations in the computationally predicted Ocn binding site, K352E and H355P, prevent Ocn activation of GPRC6A. These observations explain how dissimilar ligands activate GPRC6A and set the stage to develop novel molecules to activate and inhibit this previously poorly understood receptor.
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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.