Cryo-electron Microscopy Structural Study Of Heteromeric GABA_A Receptor

?-Aminobutyric acid(GABA)is a major inhibitory neurotransmitter in central nervous system(CNS).?-Aminobutyric acid type A(GABAA)receptors,located in synaptic and extrasynaptic,mediate rapid inhibitory neurotransmission by opening a chloride selective pore in response to binding of GABA,and thus are vital for controlling excitability in the brain.GABAA receptors trafficking can cause neurological disorders like epilepsy,drug abuse and schizophrenia.There are numbers of binding sites that can modulate the activity of the receptor,occupied by GABA,benzodiazepines,neuroactive steroids,propofol,ethanol,picrotoxin,bicuculline and over hundreds of pharmacologically and clinically important compouds.As a member of Cys loop-type pentameric ligand-gated ion channel(pLGICs)superfamily,GABAA receptors are heteropentamers comprising of 19 subunits:?1-6,?1-3,?1-3,?1-3,?,?,? and ?,typically consisting of ?/?/?subunit combinations.GABAAA receptors have distinct biophysical and pharmacological properties with different subunit compositions and arrangements.Although the subunit stoichiometries and arrangements of GABAA receptor subtypes have been intensively investigated in the last two decades,the assembling principles of these receptor subtypes remain unknown.Moreover,GABA ligand binding site in the ?/? subunit interface and the working mechanism of the receptors are unclear.Here we present the structure of the ?5?3 GABAA receptor in complex with GABA,determined by single particle cryo-EM at 3.51 A resolution.The receptor represents an activated conformation around an open pore,with a subunit combination of one a subunit and four ? subunits.This study reveals the three-dimensional structure of?5?3 GABAA receptor at atomic resolution,identifies ligands binding site and open state,and provides structure information for related disease treatment in clinical practice.