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Editorial
. 2019 Jul;7(Suppl 3):S144.
doi: 10.21037/atm.2019.06.23.

Cryo-electron microscopy reveals informative details of GABAA receptor structural pharmacology: implications for drug discovery

Richard W Olsen  1 , A Kerstin Lindemeyer  1 , Martin Wallner  1 , Xiaorun Li  2 , Kevin W Huynh  2 , Z Hong Zhou  2
Affiliations
Editorial

Cryo-electron microscopy reveals informative details of GABAA receptor structural pharmacology: implications for drug discovery

Richard W Olsen et al. Ann Transl Med. 2019 Jul.
No abstract available

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Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Structure of the α1(red)β3(blue)γ2(yellow) GABAR viewed from the extracellular side (left) and a side view, parallel to the membrane (right) with only three subunits shown. Note the new nomenclature in which each of five subunits has a unique identifier-clockwise α1-A, β3-B, y2-C, α1-D, β3-E. The picrotoxin (PTX) pore binding/blocking site is boxed. ligand binding sites at subunit interfaces (β3+/α1-, GABA, bicuculline) are shown as green ovals, α1+/γ2- benzodiazepine site denoted by blue ovals, and potential “orphan” ligand sites (α1+/β3-, γ2+/β3-) are indicated in orange. Megabody 38 (Mb38) binds at the α1-A/β3-E subunit interface and provides the means to orient individual images. Also indicated is one of the two phosphatidylinositol 4,5-bisphosphate (PIP2) binding sites on each of the two α1 subunits. The negatively charged PIP2 phosphate groups interact with positively charged amino acids (R,K) located at the plasma membrane/cytosolic interface which are conserved in α1,2,3,5 subunits. Also shown in this structure are glycan residues (N80, N149 in β3, and N208 in the γ2 subunit) at the periphery of the extracellular domains, as well as an α1 glycan (N111) located in the pore vestibule. These N-linked glycosylation sites are conserved among all α, β, and γ subunits, which makes it likely that these glycans serve important structural/functional roles
Figure 2
Figure 2
CryoEM structural pharmacology reveals exquisite details on how ligand binding influences channel gating. (A) Schematic illustration of conformational changes leading to the open/desensitized state of GABARs upon binding of orthosteric ligands (GABA and GABA analogs) and benzodiazepine (BZ)-site allosteric modulators. Binding of GABA leads to a conformational change which leads to the opening of the Cl– conducting pore, and this is facilitated by the binding of BZs at the α+/γ2- interface. (B) Structural pharmacology reveals that classical BZs like diazepam and the imidazobenzodiazepine antagonist (flumazenil) show surprising differences in binding mode to the BZ binding site at the α1+/γ2- subunit interface. Amino acids critical for BZ binding in α1 (red) and γ2 (yellows) are shown and the structures of diazepam (blue) and flumazenil (gray) are overlaid in their binding sites. A comparison shows that the “pendant” phenyl (marked in red) of classical BZ (diazepam, alprazolam) occupies the region that in imidazobenzodiazepines (flumazenil, bretazenil) is occupied by the benzene ring of the benzodiazepine structure (bold). Modified from Masiulis et al. (1).
See this image and copyright information in PMC

Comment on

  • GABAA receptor signalling mechanisms revealed by structural pharmacology.
    Masiulis S, Desai R, Uchański T, Serna Martin I, Laverty D, Karia D, Malinauskas T, Zivanov J, Pardon E, Kotecha A, Steyaert J, Miller KW, Aricescu AR. Masiulis S, et al. Nature. 2019 Jan;565(7740):454-459. doi: 10.1038/s41586-018-0832-5. Epub 2019 Jan 2. Nature. 2019. PMID: 30602790 Free PMC article.

References

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