Discovery of NOT-GPCRs: An Archaeal Membrane Protein Family Whose AlphaFold Predictions Structurally Resemble G Protein-coupled Receptors

Sakuma, Koya

doi:10.51094/jxiv.1270

##article.authors##

Sakuma, Koya Department of Basic Biology, Cellular and Structural Physiology Institute, Nagoya University https://orcid.org/0000-0003-2083-0979

DOI:

https://doi.org/10.51094/jxiv.1270

キーワード:

Marine Group II (MGII)、 Bacteriorhodopsin (bR)、 G protein-coupled receptor (GPCR)、 Data mining、 Structure–function relationship、 AlphaFold2

抄録

G protein-coupled receptors (GPCRs) are a prominent class of membrane proteins recognized for their significance in human pharmaceutical research and central roles in eukaryotic cell communication. The author hypothesized that GPCR-like proteins might be distributed across domains other than eukaryotes and aimed to discover them via structure-based data mining. Comprehensive structure-based searches against the AlphaFold protein structure database identified a family of uncharacterized membrane proteins in Methanobacteriati (formerly Euryarchaeota) whose AlphaFold predictions structurally resemble the canonical GPCR fold. They were termed Not Objectively True GPCRs (NOT-GPCRs) because they show higher structural similarity to GPCRs than to archaerhodopsin and bacteriorhodopsin, while lacking evidence of coupling to G proteins. In addition to the GPCR-like domain, they possess putative eighth and ninth transmembrane helices on the C-terminus, and a subtype possesses EF-hand motifs in the probable cytosolic domain following them. The physiological and environmental significance of the genes remains entirely unknown. Therefore, NOT-GPCRs are structurally appealing, yet offer no biologically grounded interpretation at this stage. When seen from the viewpoint of metascience, this situation could illustrate the Rorschach limit of structural biology in the post-AlphaFold era. To ultimately reconnect the contextless atomic coordinate data to biology, experimental validation will be necessary to confirm the predictions, elucidate their functions, and uncover their evolutionary origin. Equally important will be the development of a novel interpretative framework in structural biology to reconsider the dogma Structure Determines Function.

利益相反に関する開示

The author declares that there are no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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