Ayub, Hoor, Murray, Rebecca J., Kuyler, Gestél C., Napier-Khwaja, Farhaan, Gunner, Joseph, Dafforn, Tim R., Klumperman, Bert, Poyner, David R. and Wheatley, Mark (2024). GPCRs in the round:SMA-like copolymers and SMALPs as a platform for investigating GPCRs. Archives of Biochemistry and Biophysics, 754 ,
Abstract
G-protein-coupled receptors (GPCRs) are the largest family of membrane proteins, regulate a plethora of physiological responses and are the therapeutic target for 30–40% of clinically-prescribed drugs. They are integral membrane proteins deeply embedded in the plasma membrane where they activate intracellular signalling via coupling to G-proteins and β-arrestin. GPCRs are in intimate association with the bilayer lipids and that lipid environment regulates the signalling functions of GPCRs. This complex lipid ‘landscape’ is both heterogeneous and dynamic. GPCR function is modulated by bulk membrane properties including membrane fluidity, microdomains, curvature, thickness and asymmetry but GPCRs are also regulated by specific lipid:GPCR binding, including cholesterol and anionic lipids. Understanding the molecular mechanisms whereby GPCR signalling is regulated by lipids is a very active area of research currently. A major advance in membrane protein research in recent years was the application of poly(styrene-co-maleic acid) (SMA) copolymers. These spontaneously generate SMA lipid particles (SMALPs) encapsulating membrane protein in a nano-scale disc of cell membrane, thereby removing the historical need for detergent and preserving lipid:GPCR interaction. The focus of this review is how GPCR-SMALPs are increasing our understanding of GPCR structure and function at the molecular level. Furthermore, an increasing number of ‘second generation’ SMA-like copolymers have been reported recently. These are reviewed from the context of increasing our understanding of GPCR molecular mechanisms. Moreover, their potential as a novel platform for downstream biophysical and structural analyses is assessed and looking ahead, the translational application of SMA-like copolymers to GPCR drug discovery programmes in the future is considered.
Publication DOI: | https://doi.org/10.1016/j.abb.2024.109946 |
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Divisions: | College of Health & Life Sciences > School of Biosciences College of Health & Life Sciences > Aston Pharmacy School Aston University (General) |
Funding Information: | The authors acknowledge funding support from the Biotechnology and Biological Sciences Research Council (BBSRC: BB/R016615/1 to MW and TRD; BB/R016755/1 to DRP). TRD, GCK and BK acknowledge funding from the Wellcome Trust via a Technology Development gran |
Additional Information: | Copyright © 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/) |
Uncontrolled Keywords: | SMI,SMALP,SMA,SMILP,DIBMALP,G-protein-coupled receptor (GPCR),Membrane protein,Lipids,DIBMA |
Publication ISSN: | 1096-0384 |
Last Modified: | 02 Dec 2024 09:04 |
Date Deposited: | 12 Mar 2024 08:33 |
Full Text Link: | |
Related URLs: |
https://www.sci ... 003986124000651
(Publisher URL) http://www.scop ... tnerID=8YFLogxK (Scopus URL) |
PURE Output Type: | Article |
Published Date: | 2024-04-01 |
Published Online Date: | 2024-02-22 |
Accepted Date: | 2024-02-20 |
Authors: |
Ayub, Hoor
Murray, Rebecca J. Kuyler, Gestél C. Napier-Khwaja, Farhaan Gunner, Joseph Dafforn, Tim R. Klumperman, Bert Poyner, David R. ( 0000-0003-1590-112X) Wheatley, Mark |