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bioRxiv · 10.1101/2022.09.24.508774

GPCRome-wide structural analysis of G-protein-coupling selectivity

Matic, M.·Miglionico, P.·Inoue, A.·Raimondi, F.
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Abstract

We present a comprehensive computational analysis of available 3D GPCR-G-protein complexes to inspect the structural determinants of G-protein-coupling selectivity. Analysis of the residue contacts at interaction interfaces has revealed a network of secondary structure elements recapitulating known structural hallmarks determining G-protein-coupling specificity, including TM5, TM6 and ICLs. We coded interface contacts into generic-number fingerprints to reveal specific coupling-determinant positions. Clustering of Gs vs Gi complexes is best achieved when considering both GPCR and G-protein contacting residues rather than separated representations of the interaction partners, suggesting that coupling specificity emerges as contextual residue interactions at the interface. Interestingly, Gs-GPCR complexes contain a higher number of contacts than Gi/o-GPCR complexes, likely caused by overall higher conservation and structural constraint on the Gs interface. In contrast, Gi/o proteins adopt a wider number of alternative docking poses on cognate receptors, as assessed via structural alignments of representative 3D complexes. Furthermore, binding energy calculations demonstrate that distinct structural properties of the complexes contribute to higher stability of Gs than Gi/o complexes. AlphaFold2 predictions of experimental binary complexes confirmed several of these structural features and allowed us to augment the structural coverage of poorly characterized complexes (e.g. G12/13). We propose that the structural properties of different G-protein complexes, such as structural restraining of Gs compared to Gi/o ones, could be instrumental in fine-tuning their activation and downstream signaling mechanisms. Highlights-Comprehensive structural bioinformatics analysis of available GPCR-G-protein complexes captures common as well as group-specific structural features responsible of receptor-G-protein recognition -Distinct contact patterns explain different docking modes of Gi/o vs Gs complexes, the latter being characterized by higher enrichment of characteristic contacts and lower structural variability suggestive of higher interface conservation. -Structural hallmarks are associated with different estimated binding energies, which mainly discriminates Gs versus Gi/o couplings, but which also point to class-dependent differences (e.g. Class A vs Class B) in binding the same transducer (Gs)

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Matic, M., Miglionico, P., Inoue, A., Raimondi, F.. 2022-09-26. GPCRome-wide structural analysis of G-protein-coupling selectivity. https://doi.org/10.1101/2022.09.24.508774

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