The importance of water in membrane receptor function – Implications for optogenetics-Anthony Watts

Recorded: Friday 15 November, 2024,

Where: at LINXS (Scheelevägen 19, Lund)
Title: The importance of water in membrane receptor function – Implications for optogenetics

Speaker: Anthony Watts, Emeritus Professor, Biochemistry Department, University of Oxford, UK.

ABSTRACT

Resolving conformational changes in membrane receptors in response to a stimulus, and capturing their functionally relevant dynamics, is very challenging. Over the years we have addressed this challenge using a range of spectroscopic approaches (1, 2, 3) on functionally competent photoreceptors, often in their natural membranes4 or Lipodisqs™ (5, 6). More recently, we have complemented this work with functional studies, mass spec characterization7 and very high resolution (1.07Å) crystallography (8, 9, 10) , as well as photo-induced x-ray, free electron laser studies (XFELS), without the use of detergents and including natural lipids. This high-resolution information reveals waters and their importance in both receptor activation-desensitization and QM(SCC-DFTB)/MM MD trajectories give information about the activation process. The system studied is achearhodopsin-3 (AR3), a photoreceptor utilized widely in optogenetics despite the lack of structures until now. We suggest that the different arrangement of internal water networks in AR3 is responsible for the faster photocycle kinetics compared to homologs – AR3 is ~10x more efficient than bacteriorhodopsin at current generation. These insights may well have generic implications for other receptors.

(1). Higman et al., (2011) Angew. Chemie 50(36):8432 (2). Dijkman et al., (2018) Nature Comms. 9:1710 (3). Dijkman et al., (2020) Science Advances, 6:33 (4). Lavington & Watts (2020) Biophys. Rev. 12:1287 (5). Juarez et al., (2019) Chem. Phys. Lipids 221:167 (6). Sawczyc et al (2023) Eur. Biophys J. 52:39 (7). Hoi et al., (2021) Nano Letters, 21(7):2824 (8). Axford et al., (2022) Acta Cryst D78:52 (9). Juarez et al (2021) Nature Comms. 12:629 (10). Birsh et al., (2023) J. Appl. Cryst. 56:1361

BIO

Anthony Watts (https://www.bioch.ox.ac.uk/research/w...) is a biophysicist (BSc, PhD, Biophysics, Leeds University, UK) who, after post-doctoral work at the MPI, Göttingen for biophysikalische Chemie (1975-1980), joined the faculty at the University of Oxford as a Professor of Biochemistry (1980 - 2019) and C W Maplethorpe Fellow, St Hugh’s College. He was President of EBSA (2017-2019; EBSA.ORG) and is currently President of IUPAB (2024 - 2027) (IUPAB.ORG). He has served on many national and international review bodies and Councils, and established, as Director, the National Solid State NMR Labs., RAL, Didcot, and is currently a Leverhulme Emeritus Fellow (2021 - 2024).

His research has encompassed multiple biophysical methodologies to investigate function of biological membranes, relating structure and multi-scale dynamics to function. In particular, he has studied extensively retinal proteins and GPCRs, always with functionally competent systems. In particular, he has developed novel isotopic labelling methods, including deuteration, in solid state NMR and neutron studies of lipids and ligands at target sites to yield high sub-Å resolution and functionally relevant dynamics. Most recently, XFELs data (from SACLA) is giving time-resolved information about photon induced changes in AR3 at high resolution.