6I0Q

Crystal structure of BTB domain of KCTD16 hexamer

Summary for 6I0Q

• Entry DOI: 10.2210/pdb6i0q/pdb
• Descriptor: BTB/POZ domain-containing protein KCTD16 (2 entities in total)
• Functional Keywords: kctd, gaba(b) receptor, receptor associated protein, structural protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 12176.01

Authors

Kasaragod, V.B.,Sereikaite, V.,Stromgaard, K.,Schindelin, H. (deposition date: 2018-10-26, release date: 2019-10-02, Last modification date: 2024-01-24)

Primary citation

Sereikaite, V.,Fritzius, T.,Kasaragod, V.B.,Bader, N.,Maric, H.M.,Schindelin, H.,Bettler, B.,Stromgaard, K.
Targeting the gamma-Aminobutyric Acid Type B (GABAB) Receptor Complex: Development of Inhibitors Targeting the K+Channel Tetramerization Domain (KCTD) Containing Proteins/GABABReceptor Protein-Protein Interaction.
J.Med.Chem., 62:8819-8830, 2019

PubMed Abstract: Targeting multiprotein receptor complexes, rather than receptors directly, is a promising concept in drug discovery. This is particularly relevant to the GABA 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 GABA receptor complex-the interaction with KCTD proteins. By employing the μSPOT technology, we first defined the GABA receptor-binding epitope mediating the KCTD interaction. Subsequently, we developed a highly potent peptide-based inhibitor that interferes with the KCTD/GABA 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 GABA receptor complex, revealing a fundamentally novel approach for targeting GABA receptor-associated neuropsychiatric disorders.

PubMed: 31509708
DOI: 10.1021/acs.jmedchem.9b01087

Experimental method

X-RAY DIFFRACTION (2.3 Å)