6M8S
Crystal structure of the KCTD12 H1 domain in complex with Gbeta1gamma2 subunits
Summary for 6M8S
| Entry DOI | 10.2210/pdb6m8s/pdb |
| Related | 6M8R |
| Descriptor | Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, BTB/POZ domain-containing protein KCTD12 (3 entities in total) |
| Functional Keywords | beta-propeller, homopentamer, gabab desensitization, signaling protein |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 15 |
| Total formula weight | 304886.23 |
| Authors | Zheng, S.,Kruse, A.C. (deposition date: 2018-08-22, release date: 2019-02-27, Last modification date: 2023-10-11) |
| Primary citation | Zheng, S.,Abreu, N.,Levitz, J.,Kruse, A.C. Structural basis for KCTD-mediated rapid desensitization of GABABsignalling. Nature, 567:127-131, 2019 Cited by PubMed Abstract: The GABA (γ-aminobutyric acid type B) receptor is one of the principal inhibitory neurotransmitter receptors in the brain, and it signals through heterotrimeric G proteins to activate a variety of effectors, including G-protein-coupled inwardly rectifying potassium channels (GIRKs). GABA-receptor signalling is tightly regulated by auxiliary subunits called KCTDs, which control the kinetics of GIRK activation and desensitization. However, the mechanistic basis for KCTD modulation of GABA signalling remains incompletely understood. Here, using a combination of X-ray crystallography, electron microscopy, and functional and biochemical experiments, we reveal the molecular details of KCTD binding to both GABA receptors and G-protein βγ subunits. KCTDs associate with the receptor by forming an asymmetric pentameric ring around a region of the receptor carboxy-terminal tail, while a second KCTD domain, H1, engages in a symmetric interaction with five copies of Gβγ in which the G-protein subunits also interact directly with one another. We further show that KCTD binding to Gβγ is highly cooperative, defining a model in which KCTD proteins cooperatively strip G proteins from GIRK channels to induce rapid desensitization following receptor activation. These results provide a framework for understanding the molecular basis for the precise temporal control of GABA signalling by KCTD proteins. PubMed: 30814734DOI: 10.1038/s41586-019-0990-0 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.71 Å) |
Structure validation
Download full validation report
