Recent progress in structural studies on TMEM16A channel

Figures

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  Fig. 1. TMEM16A as a drug target. Scheme of possible pharmacological effects (blue: inhibitors; red: activators) of TMEM16A modulators. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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  Fig. 2. The molecular architecture of TMEM16A. (a-b) Cartoon representation of overlap of the Ca2+-bound structure of TMEM16A channel (cyan) with lipid scrambler (nhTMEM16; gray). (c) The pore domain of TMEM16A, the pores are shown by a gray grid. (d) Ca2+ binding sites. (e) PI(4,5)P2 binding sites. For the sake of clarity, key amino acids are marked as sticks and only the amino acids that can be displayed on this side are shown. (f) Electrostatic surface of TMEM16A. Red (−50 kT/e); blue (+50 kT/e). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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  Fig. 3. Cartoon representation of overlap between different states of TMEM16 member. (a) Ca2+-free structure (magenta) of TMEM16A vs the Ca2+-bound structure (cyan) of it. (b) Ca2+-free structure (blue) of afTMEM16 vs the Ca2+-bound structure (red) of it. (c) Open state (orange) of nhTMEM16 vs the close state (forest) of it. (d) Ca2+-free structure (gray) of hTMEM16k vs the Ca2+-bound structure (greencyan) of it. (e) Close state (ruby) of mTMEM16F vs the intermediate state (green) of it. (f) Ca2+-free structure (lightpink) of hTMEM16F vs the Ca2+-bound structure (yellow) of it. The direction indicated by the arrow is the ion channel or lipid scramblases from closed to open. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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  Fig. 4. Modulators of TMEM16A. (a) Modulator binding sites. Cartoon representation of TMEM16A in which key amino acids are marked as sticks. The two subunits of the TMEM16A are distinguished by magenta and cyan, respectively. The drug name is shown in bold font. (b) The flowchart of virtual screening. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)