1.A.9.5.14 GABAAR beta subunit of 474 aas and 4 TMSs in a 3 + 1 TMS arrangement. γ-aminobutyric acid type A receptors (GABAARs) are ligand gated channels mediating inhibition in the central nervous system. Garifulina et al. 2022 identified a previouly undescribed function of beta-subunit homomers as proton-gated anion channels. Mutation of a single H267A in beta3 subunits completely abolished channel activation by protons. In molecular dynamic simulations of the beta3 crystal structure, protonation of H267 increased the formation of hydrogen bonds between H267 and E270 of the adjacent subunit, leading to a pore stabilising ring formation and accumulation of Cl- within the transmembrane pore. Conversion of these residues in proton insensitive rho1 subunits transfered proton-dependent gating, thus highlighting the role of this interaction in proton sensitivity. Activation of chloride and bicarbonate currents at physiological pH, and kinetic studies, suggest a physiological role in neuronal and non-neuronal tissues that express beta subunits, and thus they are potential novel drug target (Garifulina et al. 2022). Residues in the 1st TMS are important for GABAArho receptor function (Crowther et al. 2022).
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Accession Number: | 5O8F_E |
Protein Name: | E Chain E, Gamma-aminobutyric acid receptor subunit beta-3,Gamma-aminobutyric acid receptor subunit alpha-5,Gamma-aminobutyric acid receptor subunit alpha-5 |
Length: | 368 |
Molecular Weight: | |
Species: | Homo sapiens [9606] |
Number of TMSs: | 4 |
Substrate |
chloride, hydrogencarbonate |
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1: ETGQSVNDPG NMSFVKETVD KLLKGYDIRL RPDFGGPPVC VGMNIDIASI DMVSEVNMDY
61: TLTMYFQQYW RDKRLAYSGI PLNLTLDNRV ADQLWVPDTY FLNDKKSFVH GVTVKNRMIR
121: LHPDGTVLYG LRITTTAACM MDLRRYPLDE QNCTLEIESY GYTTDDIEFY WRGGDKAVTG
181: VERIELPQFS IVEHRLVSRN VVFATGAYPR LSLSFRLKRN IGYFVIQTYL PCIMTVILSQ
241: VSFWLNRESV PARTVFGVTT VLTMTTLSIS ARNSLPKVAY ATAMDWFIAV CYAFVFSALI
301: EFATVNYFTK SQPARAAKID KMSRIVFPIL FGTFNLVYWA TYLNREPVIK GATSPKGTTE
361: TSQVAPA