Targeting the γ‑Aminobutyric Acid Type B (GABA_B) Receptor Complex: Development of Inhibitors Targeting the K⁺ Channel Tetramerization Domain (KCTD) Containing Proteins/GABA_B Receptor Protein–Protein Interaction

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 μSPOT 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.