TY - JOUR

T1 - A unified model of the GABAA receptor comprising agonsit and benzodiazepine binding sites

AU - Bergmann, Rikke

AU - Kongsbak, Kristine Grønning

AU - Sørensen, Pernille Louise

AU - Sander, Tommy

AU - Balle, Thomas

PY - 2013/1/7

Y1 - 2013/1/7

N2 - We present a full-length a1b2c2 GABA receptor model optimized for agonists and benzodiazepine (BZD) allostericmodulators. We propose binding hypotheses for the agonists GABA, muscimol and THIP and for the allosteric modulatordiazepam (DZP). The receptor model is primarily based on the glutamate-gated chloride channel (GluCl) from C. elegans andincludes additional structural information from the prokaryotic ligand-gated ion channel ELIC in a few regions. Availablemutational data of the binding sites are well explained by the model and the proposed ligand binding poses. We suggest aGABA binding mode similar to the binding mode of glutamate in the GluCl X-ray structure. Key interactions are predictedwith residues a1R66, b2T202, a1T129, b2E155, b2Y205 and the backbone of b2S156. Muscimol is predicted to bind similarly,however, with minor differences rationalized with quantum mechanical energy calculations. Muscimol key interactions arepredicted to be a1R66, b2T202, a1T129, b2E155, b2Y205 and b2F200. Furthermore, we argue that a water molecule couldmediate further interactions between muscimol and the backbone of b2S156 and b2Y157. DZP is predicted to bind withinteractions comparable to those of the agonists in the orthosteric site. The carbonyl group of DZP is predicted to interactwith two threonines a1T206 and c2T142, similar to the acidic moiety of GABA. The chlorine atom of DZP is placed near theimportant a1H101 and the N-methyl group near a1Y159, a1T206, and a1Y209. We present a binding mode of DZP in whichthe pending phenyl moiety of DZP is buried in the binding pocket and thus shielded from solvent exposure. Our full lengthGABAA receptor is made available as Model S1.

AB - We present a full-length a1b2c2 GABA receptor model optimized for agonists and benzodiazepine (BZD) allostericmodulators. We propose binding hypotheses for the agonists GABA, muscimol and THIP and for the allosteric modulatordiazepam (DZP). The receptor model is primarily based on the glutamate-gated chloride channel (GluCl) from C. elegans andincludes additional structural information from the prokaryotic ligand-gated ion channel ELIC in a few regions. Availablemutational data of the binding sites are well explained by the model and the proposed ligand binding poses. We suggest aGABA binding mode similar to the binding mode of glutamate in the GluCl X-ray structure. Key interactions are predictedwith residues a1R66, b2T202, a1T129, b2E155, b2Y205 and the backbone of b2S156. Muscimol is predicted to bind similarly,however, with minor differences rationalized with quantum mechanical energy calculations. Muscimol key interactions arepredicted to be a1R66, b2T202, a1T129, b2E155, b2Y205 and b2F200. Furthermore, we argue that a water molecule couldmediate further interactions between muscimol and the backbone of b2S156 and b2Y157. DZP is predicted to bind withinteractions comparable to those of the agonists in the orthosteric site. The carbonyl group of DZP is predicted to interactwith two threonines a1T206 and c2T142, similar to the acidic moiety of GABA. The chlorine atom of DZP is placed near theimportant a1H101 and the N-methyl group near a1Y159, a1T206, and a1Y209. We present a binding mode of DZP in whichthe pending phenyl moiety of DZP is buried in the binding pocket and thus shielded from solvent exposure. Our full lengthGABAA receptor is made available as Model S1.

U2 - 10.1371/journal.pone.0052323

DO - 10.1371/journal.pone.0052323

M3 - Journal article

C2 - 23308109

VL - 8

SP - e52323

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 1

ER -