Structure of human GABAB receptor in an inactive state
Jinseo Park1, Ziao Fu2, Aurel Frangaj1
1Department of Pharmacology, Columbia University, New York, NY, USA.
Nature
|June 26, 2020
Summary
The GABAB receptor
Area of Science:
- Neuroscience
- Molecular Biology
- Structural Biology
Background:
- The GABAB receptor, a class C G-protein-coupled receptor (GPCR), is crucial for inhibitory neurotransmission and linked to neurological conditions.
- It functions as a heterodimer of GABAB1 and GABAB2 subunits, each with distinct roles in ligand recognition and G-protein coupling.
- The full-length structure and transmembrane signaling mechanism of this essential receptor remained elusive.
Purpose of the Study:
- To determine the near full-length structure of the human GABAB receptor.
- To elucidate the structural basis of its inactive conformation and transmembrane signaling.
- To identify novel structural features and their functional implications.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was employed to capture the near full-length GABAB receptor structure.
- Structural analysis focused on identifying ligands, subunit interfaces, and key conformational states.
- Functional assays were used to investigate the role of identified structural elements.
Main Results:
- A near full-length structure of the GABAB receptor in an inactive state was resolved.
- Two endogenous phospholipids were found embedded in the transmembrane domains, stabilizing the receptor.
- A novel heterodimer interface between transmembrane helices 3 and 5, featuring an 'intersubunit latch,' was identified as critical for the inactive conformation.
Conclusions:
- The determined structure provides unprecedented insight into the inactive state of the GABAB receptor.
- The transmembrane interface and 'intersubunit latch' are key determinants of receptor quiescence.
- Disruption of this interface leads to constitutive receptor activity, highlighting its importance in regulating GABAergic signaling.
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