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Publication Abstract from PubMed

Targeting multiprotein receptor complexes, rather than receptors directly, is a promising concept in drug discovery. This is particularly relevant to the GABAB receptor complex, which plays a prominent role in many brain functions and diseases. Here, we provide the first studies targeting a key protein-protein interaction of the GABAB receptor complex-the interaction with KCTD proteins. By employing the muSPOT technology, we first defined the GABAB receptor-binding epitope mediating the KCTD interaction. Subsequently, we developed a highly potent peptide-based inhibitor that interferes with the KCTD/GABAB receptor complex and efficiently isolates endogenous KCTD proteins from mouse brain lysates. X-ray crystallography and SEC-MALS revealed inhibitor induced oligomerization of KCTD16 into a distinct hexameric structure. Thus, we provide a template for modulating the GABAB receptor complex, revealing a fundamentally novel approach for targeting GABAB receptor-associated neuropsychiatric disorders.

Targeting the gamma-Aminobutyric Acid Type B (GABAB) Receptor Complex: Development of Inhibitors Targeting the K(+) Channel Tetramerization Domain (KCTD) Containing Proteins/GABAB Receptor Protein-Protein Interaction.,Sereikaite V, Fritzius T, Kasaragod VB, Bader N, Maric HM, Schindelin H, Bettler B, Stromgaard K J Med Chem. 2019 Sep 25. doi: 10.1021/acs.jmedchem.9b01087. PMID:31509708^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.