Structures of the archaerhodopsin-3 transporter reveal that disordering of internal water networks underpins receptor sensitization

Juan F. Bada Juarez, Peter J. Judge, Suliman Adam, Danny Axford, Javier Vinals, James Birch, Tristan O.C. Kwan, Kin Kuan Hoi, Hsin Yung Yen, Anthony Vial, Pierre Emmanuel Milhiet, Carol V. Robinson, Igor Schapiro, Isabel Moraes*, Anthony Watts*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


Many transmembrane receptors have a desensitized state, in which they are unable to respond to external stimuli. The family of microbial rhodopsin proteins includes one such group of receptors, whose inactive or dark-adapted (DA) state is established in the prolonged absence of light. Here, we present high-resolution crystal structures of the ground (light-adapted) and DA states of Archaerhodopsin-3 (AR3), solved to 1.1 Å and 1.3 Å resolution respectively. We observe significant differences between the two states in the dynamics of water molecules that are coupled via H-bonds to the retinal Schiff Base. Supporting QM/MM calculations reveal how the DA state permits a thermodynamic equilibrium between retinal isomers to be established, and how this same change is prevented in the ground state in the absence of light. We suggest that the different arrangement of internal water networks in AR3 is responsible for the faster photocycle kinetics compared to homologs.

Original languageAmerican English
Article number629
JournalNature Communications
Issue number1
StatePublished - 27 Jan 2021

Bibliographical note

Funding Information:
We thank Dr. Robin Owen and Dr. Darren Sherrell, and the I24 beamline staff (Diamond Light Source) for their support during data collection under the MX proposals 19152 and 11386. We thank Juan Escobar and Peter Fisher (Oxford) for technical assistance, and Dr. Agata Butryn (Diamond Light Source) and Dr Rosana Reis (NPL) for helpful discussions. We are grateful for support from the Membrane Protein Laboratory under Wellcome Trust grant number 20289/Z16/Z, including the award of experimental time (SM15222) on the B23 Beamline at Diamond Light Source (UK) and we acknowledge the support of Dr. Giuliano Siligardi, Dr. Rohanah Hussain and Dr. Charlotte Hughes. We acknowledge funding from United Kingdom Department of Business, Energy and Industrial Strategy (BEIS) to I.M., from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (Grant Agreement number 678169, ERC Starting Grant “PhotoMutant”) to I.S., from DSTL UK (grant number DSTLX-1000099768) and BBSRC (grant number BB/N006011/1) to A.W. We thank the Minerva Stiftung for a post-doctoral fellowship within the framework of the Minerva Fellowship Program to SA and the DFG for a Mercator Fellowship to I.S. (Grant number SFB 1078).

Publisher Copyright:
© 2021, Crown.


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