Author response: High-resolution deep mutational scanning of the melanocortin-4 receptor enables target characterization for drug discovery
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Mutations skewing MC4R signalling and mutations selectively disrupting agonist binding were both identified.
“Mutations skewing MC4R signalling and mutations selectively disrupting agonist binding were both identified, informing on mechanisms of ligand binding and signal transduction.”
From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [109]
The public review in our copy (section labeled “28 citations”; no page given) says the authors identified variants that bias MC4R signaling and variants that disrupt activation by one agonist but not another. It describes an effect on agonist binding as a hypothesis, not an established finding that the mutations selectively disrupt binding. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe MC4R MAVE mapped the response of MC4R variants to two types of drugs with both Gs and Gq-mediated effects.
“Using this approach, the response of MC4R variants to two types of drugs with both Gs and Gq-mediated effects was mapped (109).”
From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [109]
The public review in the author response (section “28 citations,” page not specified) says the MC4R deep mutational scan mapped how variants affect activation by different small-molecule agonists, including variants that distinguish one agonist from another. It also describes Gs and Gq signaling assays, but does not establish that both drugs’ effects were mapped through both pathways. (LLM, conf=0.83)
Experimental — accuracy not yet measuredTwo GPCRs of endocrine interest have been subjected to MAVEs to date.
“Two GPCRs of endocrine interest have been subjected to MAVEs to date.”
From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [109]
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Massively parallel functional genomic assays in endocrinology: from promise to delivery
Xu, J., Aslanzadeh, V., Kudla, G., & Semple, R. K. (2026) · Journal of Molecular Endocrinology · doi:10.1530/jme-25-0134
- Authors
- Howard, C. J., Abell, N. S., Osuna, B. A., Jones, E. M., Chan, L. Y., Chan, H., Artis, D. R., Asfaha, J. B., Bloom, J. S., Cooper, A. R., Liao, A., Mahdavi, E., Mohammed, N., Su, A. L., Uribe, G. A., Kosuri, S., Dickel, D. E., & Lubock, N. B.
- Affiliations
- Octant, Inc.
- University of California, San Francisco (US)
- University of California, Los Angeles (US)
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2025-04-09
- ISSN
- 2050-084X (ISSN-L)
- OpenAlex
- W4409279412
- Cited by
- 0
- References
- 0
- Type
- peer review
- Language
- en
- Open access
- gold
- doi.org
- Locations
- eLife (publishedVersion, cc-by)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- melanocortin-4 receptor, deep mutational scanning, biased signaling, ligand binding, receptor isoforms, obesity treatment
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