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Nature. 2018 Sep;561(7723):349-354. doi: 10.1038/s41586-018-0504-5. Epub 2018 Aug 29.

Structural mechanisms of selectivity and gating in anion channelrhodopsins.

Kato HE1,2, Kim YS3,4,5, Paggi JM6,7, Evans KE3,4,5, Allen WE3,4,5, Richardson C6, Inoue K8,9,10, Ito S9, Ramakrishnan C3,4,5, Fenno LE3,4,5, Yamashita K11, Hilger D12, Lee SY3,4,5, Berndt A3,4,5, Shen K13,5, Kandori H9,10, Dror RO6,7, Kobilka BK12, Deisseroth K14,15,16.

Author information

1
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. hekato@stanford.edu.
2
PRESTO, Japan Science and Technology Agency, Kawaguchi, Japan. hekato@stanford.edu.
3
Department of Bioengineering, Stanford University, Stanford, CA, USA.
4
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
5
Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
6
Department of Computer Science, Stanford University, Stanford, CA, USA.
7
Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA.
8
PRESTO, Japan Science and Technology Agency, Kawaguchi, Japan.
9
Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Nagoya, Japan.
10
OptoBioTechnology Research Center, Nagoya Institute of Technology, Nagoya, Japan.
11
RIKEN SPring-8 Center, Hyogo, Japan.
12
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
13
Department of Biology, Stanford University, Stanford, CA, USA.
14
Department of Bioengineering, Stanford University, Stanford, CA, USA. deissero@stanford.edu.
15
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. deissero@stanford.edu.
16
Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA. deissero@stanford.edu.

Abstract

Both designed and natural anion-conducting channelrhodopsins (dACRs and nACRs, respectively) have been widely applied in optogenetics (enabling selective inhibition of target-cell activity during animal behaviour studies), but each class exhibits performance limitations, underscoring trade-offs in channel structure-function relationships. Therefore, molecular and structural insights into dACRs and nACRs will be critical not only for understanding the fundamental mechanisms of these light-gated anion channels, but also to create next-generation optogenetic tools. Here we report crystal structures of the dACR iC++, along with spectroscopic, electrophysiological and computational analyses that provide unexpected insights into pH dependence, substrate recognition, channel gating and ion selectivity of both dACRs and nACRs. These results enabled us to create an anion-conducting channelrhodopsin integrating the key features of large photocurrent and fast kinetics alongside exclusive anion selectivity.

PMID:
30158697
PMCID:
PMC6317992
DOI:
10.1038/s41586-018-0504-5
[Indexed for MEDLINE]
Free PMC Article

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