5O8F

Structure of a chimaeric beta3-alpha5 GABAA receptor in complex with nanobody Nb25 and pregnanolone

Summary for 5O8F

• Entry DOI: 10.2210/pdb5o8f/pdb
• Descriptor: Gamma-aminobutyric acid receptor subunit beta-3,Gamma-aminobutyric acid receptor subunit alpha-5,Gamma-aminobutyric acid receptor subunit alpha-5, Nanobody Nb25, alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: gabaa receptor, pregnanolone, nanobody complex, neurosteroid, ion channel, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 10
• Total formula weight: 285317.35

Authors

Miller, P.S.,Scott, S.,Masiulis, S.,De Colibus, L.,Pardon, E.,Steyaert, J.,Aricescu, A.R. (deposition date: 2017-06-13, release date: 2017-11-01, Last modification date: 2024-11-06)

Primary citation

Miller, P.S.,Scott, S.,Masiulis, S.,De Colibus, L.,Pardon, E.,Steyaert, J.,Aricescu, A.R.
Structural basis for GABAA receptor potentiation by neurosteroids.
Nat. Struct. Mol. Biol., 24:986-992, 2017

PubMed Abstract: Type A γ-aminobutyric acid receptors (GABARs) are the principal mediators of inhibitory neurotransmission in the human brain. Endogenous neurosteroids interact with GABARs to regulate acute and chronic anxiety and are potent sedative, analgesic, anticonvulsant and anesthetic agents. Their mode of binding and mechanism of receptor potentiation, however, remain unknown. Here we report crystal structures of a chimeric GABAR construct in apo and pregnanolone-bound states. The neurosteroid-binding site is mechanically coupled to the helices lining the ion channel pore and modulates the desensitization-gate conformation. We demonstrate that the equivalent site is responsible for physiological, heteromeric GABAR potentiation and explain the contrasting modulatory properties of 3a versus 3b neurosteroid epimers. These results illustrate how peripheral lipid ligands can regulate the desensitization gate of GABARs, a process of broad relevance to pentameric ligand-gated ion channels.

PubMed: 28991263
DOI: 10.1038/nsmb.3484

Experimental method

X-RAY DIFFRACTION (3.2 Å)