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The controversial issues regarding the direct interaction of melatonin toward ROR receptors have prompted us to investigate the potential melatonin binding sites on different ROR isoforms. We adopted computational and biophysical approaches to investigate the potential of melatonin as the ligand for RORs, in particular ROR\u03b2. Herein, possible melatonin binding sites were predicted by molecular docking on human RORs. The results showed that melatonin might be able to bind within the ligand-binding domain (LBD) of all RORs, despite their difference in sequence homology. The predicted melatonin binding scores were comparable to binding energies with respect to those of melatonin interaction to the well-characterized membrane receptors, MT1 and MT2. Although the computational analyses suggested the binding potential of melatonin to the LBD of ROR\u03b2, biophysical validation failed to confirm the binding. Melatonin was unable to alter the stability of human ROR\u03b2 as shown by the unaltered melting temperatures upon melatonin administration in differential scanning fluorometry (DSF). A thermodynamic isothermal titration calorimetry (ITC) profile showed that melatonin did not interact with human ROR\u03b2 in solutions, even in the presence of SRC-1 co-activator peptide. Although the direct interaction between the LBD of ROR\u03b2 could not be established, ROR\u03b1 and ROR\u03b2 gene expressions were increased upon 24\u00a0h treatment with \u03bcM-range melatonin. Our data, thus, support the studies that the nuclear effects of melatonin may not be directly mediated via its interaction with the ROR\u03b2. These findings warrant further investigation on how melatonin interacts with ROR signaling and urge the melatonin research community for a paradigm shift in the direct interaction of melatonin toward RORs. The quest to identify nuclear receptors for melatonin in neuronal cells remains valid for the community to achieve.<\/jats:p>","DOI":"10.1007\/s12035-024-04395-y","type":"journal-article","created":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T05:05:40Z","timestamp":1722920740000},"page":"2333-2347","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A Complex Interplay Between Melatonin and ROR\u03b2: ROR\u03b2 is Unlikely a Putative Receptor for Melatonin as Revealed by Biophysical Assays"],"prefix":"10.1007","volume":"62","author":[{"given":"Jiraporn","family":"Panmanee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sitthivut","family":"Charoensutthivarakul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chew Weng","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kornkanok","family":"Promthep","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujira","family":"Mukda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya","family":"Prasertporn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chutikorn","family":"Nopparat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kittitat","family":"Teerapo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Promsup","family":"Supcharoen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nopphon","family":"Petchyam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Banthit","family":"Chetsawang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piyarat","family":"Govitrapong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7736-7500","authenticated-orcid":false,"given":"Matthew","family":"Phanchana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,8,6]]},"reference":[{"issue":"2","key":"4395_CR1","first-page":"194","volume":"3","author":"R Hardeland","year":"2012","unstructured":"Hardeland R (2012) Melatonin in aging and disease -multiple consequences of reduced secretion, options and limits of treatment. 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