| Structural highlights
8oqa is a 5 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | Electron Microscopy, Resolution 2.9Å |
| Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
GBRR1_HUMAN Rho subunit of the pentameric ligand-gated chloride channels responsible for mediating the effects of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain (PubMed:37659407). Rho-containing GABA-gated chloride channels are a subclass of GABA(A) receptors (GABAARs) entirely composed of rho subunits, where GABA molecules bind at the rho intersubunit interfaces (PubMed:37659407). When activated by GABA, rho-GABAARs selectively allow the flow of chloride anions across the cell membrane down their electrochemical gradient (PubMed:37659407). Rho-1 subunits are primarily expressed in retina where rho-1-containing GABAARs may play a role in retinal neurotransmission (PubMed:1849271). Rho-1 GABAARs are also involved in neuronal tonic (extrasynaptic) and phasic (synaptic) transmission in the Purkinje neurons of the cerebellum (By similarity). Rho-1 GABAARs may also contribute to the regulation of glial development in the cerebellum by controlling extrasynaptic transmission (By similarity).[UniProtKB:P56475][1] [2]
Publication Abstract from PubMed
The neurotransmitter gamma-aminobutyric acid (GABA) drives critical inhibitory processes in and beyond the nervous system, partly via ionotropic type-A receptors (GABA(A)Rs). Pharmacological properties of rho-type GABA(A)Rs are particularly distinctive, yet the structural basis for their specialization remains unclear. Here, we present cryo-EM structures of a lipid-embedded human rho1 GABA(A)R, including a partial intracellular domain, under apo, inhibited, and desensitized conditions. An apparent resting state, determined first in the absence of modulators, was recapitulated with the specific inhibitor (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid and blocker picrotoxin and provided a rationale for bicuculline insensitivity. Comparative structures, mutant recordings, and molecular simulations with and without GABA further explained the sensitized but slower activation of rho1 relative to canonical subtypes. Combining GABA with picrotoxin also captured an apparent uncoupled intermediate state. This work reveals structural mechanisms of gating and modulation with applications to rho-specific pharmaceutical design and to our biophysical understanding of ligand-gated ion channels.
Structure and dynamics of differential ligand binding in the human rho-type GABA(A) receptor.,Cowgill J, Fan C, Haloi N, Tobiasson V, Zhuang Y, Howard RJ, Lindahl E Neuron. 2023 Nov 1;111(21):3450-3464.e5. doi: 10.1016/j.neuron.2023.08.006. Epub , 2023 Sep 1. PMID:37659407[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Cutting GR, Lu L, O'Hara BF, Kasch LM, Montrose-Rafizadeh C, Donovan DM, Shimada S, Antonarakis SE, Guggino WB, Uhl GR, et al.. Cloning of the gamma-aminobutyric acid (GABA) rho 1 cDNA: a GABA receptor subunit highly expressed in the retina. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2673-7. PMID:1849271 doi:10.1073/pnas.88.7.2673
- ↑ Cowgill J, Fan C, Haloi N, Tobiasson V, Zhuang Y, Howard RJ, Lindahl E. Structure and dynamics of differential ligand binding in the human ρ-type GABA(A) receptor. Neuron. 2023 Nov 1;111(21):3450-3464.e5. PMID:37659407 doi:10.1016/j.neuron.2023.08.006
- ↑ Cowgill J, Fan C, Haloi N, Tobiasson V, Zhuang Y, Howard RJ, Lindahl E. Structure and dynamics of differential ligand binding in the human ρ-type GABA(A) receptor. Neuron. 2023 Nov 1;111(21):3450-3464.e5. PMID:37659407 doi:10.1016/j.neuron.2023.08.006
|
