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TitleTargeting mGlyR with nanobodies for depression.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Page 831, Year 2026
Publish dateJan 26, 2026
AuthorsThibaut Laboute / Stefano Zucca / Omar K Sial / Mansi Sharma / Gloria Brunori / Shikha Singh / K V Nageswar / Haiyong Peng / Christoph Rader / Jérôme Aj Becker / Julie Le Merrer / Appu K Singh / Kirill A Martemyanov /
PubMed AbstractDevelopment of therapies for neuropsychiatric conditions is one of the greatest challenges of modern medicine. Common limitations of traditional small molecule drugs include poor efficacy, off-target ...Development of therapies for neuropsychiatric conditions is one of the greatest challenges of modern medicine. Common limitations of traditional small molecule drugs include poor efficacy, off-target side effects and difficult druggability of many targets. In this study, we report a different approach deploying small engineered single domain antibodies, known as nanobodies, for the treatment of depression, a prevalent neuropsychiatric condition. We develop highly selective nanobodies for a recently discovered glycine receptor mGlyR crucially linked to pathophysiology of depression. Using a mouse model of stress-induced depression, we show that non-invasive intranasal delivery of nanobody produces rapid and lasting anti-depressant effect. We solve an atomic structure of mGlyR bound to nanobody and use a variety of cell-based approaches to reveal the mechanism of mGlyR modulation and its impact on neural circuitry. These findings support development of biologics for the treatment of intractable brain disorders.
External linksNat Commun / PubMed:41588006 / PubMed Central
MethodsEM (single particle)
Resolution3.47 Å
Structure data

65225

9vor

EMDB-65225, PDB-9vor:
Cryo-EM Structure of Human GPR158 Bound to Nanobody Nb20
Method: EM (single particle) / Resolution: 3.47 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL

ChemComp-PEE:
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE, phospholipid*YM

ChemComp-PIE:
1,2-DIACYL-SN-GLYCERO-3-PHOSPHOINOSITOL

Source
  • homo sapiens (human)
  • lama glama (llama)
KeywordsMEMBRANE PROTEIN / GPCR / orphan receptor / nanobody / RGS proteins / signalling receptor

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