Abstract
We present a full-length a1b2c2 GABA receptor model optimized for agonists and benzodiazepine (BZD) allosteric
modulators. We propose binding hypotheses for the agonists GABA, muscimol and THIP and for the allosteric modulator
diazepam (DZP). The receptor model is primarily based on the glutamate-gated chloride channel (GluCl) from C. elegans and
includes additional structural information from the prokaryotic ligand-gated ion channel ELIC in a few regions. Available
mutational data of the binding sites are well explained by the model and the proposed ligand binding poses. We suggest a
GABA binding mode similar to the binding mode of glutamate in the GluCl X-ray structure. Key interactions are predicted
with 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 are
predicted to be a1R66, b2T202, a1T129, b2E155, b2Y205 and b2F200. Furthermore, we argue that a water molecule could
mediate further interactions between muscimol and the backbone of b2S156 and b2Y157. DZP is predicted to bind with
interactions comparable to those of the agonists in the orthosteric site. The carbonyl group of DZP is predicted to interact
with two threonines a1T206 and c2T142, similar to the acidic moiety of GABA. The chlorine atom of DZP is placed near the
important a1H101 and the N-methyl group near a1Y159, a1T206, and a1Y209. We present a binding mode of DZP in which
the pending phenyl moiety of DZP is buried in the binding pocket and thus shielded from solvent exposure. Our full length
GABAA receptor is made available as Model S1.
modulators. We propose binding hypotheses for the agonists GABA, muscimol and THIP and for the allosteric modulator
diazepam (DZP). The receptor model is primarily based on the glutamate-gated chloride channel (GluCl) from C. elegans and
includes additional structural information from the prokaryotic ligand-gated ion channel ELIC in a few regions. Available
mutational data of the binding sites are well explained by the model and the proposed ligand binding poses. We suggest a
GABA binding mode similar to the binding mode of glutamate in the GluCl X-ray structure. Key interactions are predicted
with 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 are
predicted to be a1R66, b2T202, a1T129, b2E155, b2Y205 and b2F200. Furthermore, we argue that a water molecule could
mediate further interactions between muscimol and the backbone of b2S156 and b2Y157. DZP is predicted to bind with
interactions comparable to those of the agonists in the orthosteric site. The carbonyl group of DZP is predicted to interact
with two threonines a1T206 and c2T142, similar to the acidic moiety of GABA. The chlorine atom of DZP is placed near the
important a1H101 and the N-methyl group near a1Y159, a1T206, and a1Y209. We present a binding mode of DZP in which
the pending phenyl moiety of DZP is buried in the binding pocket and thus shielded from solvent exposure. Our full length
GABAA receptor is made available as Model S1.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | P L o S One |
| Vol/bind | 8 |
| Udgave nummer | 1 |
| Sider (fra-til) | e52323 |
| Antal sider | 13 |
| ISSN | 1932-6203 |
| DOI | |
| Status | Udgivet - 7 jan. 2013 |