GPCRs steer Gi and Gs selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors

Huang, Sijie; Xu, Peiyu; Shen, Dan‐Dan; Simón, I; Mao, Chunyou; Tan, Yangxia; Zhang, Huibing; Harpsøe, Kasper; Li, Huadong; Zhang, Yumu; You, Chongzhao; Yu, Xuekui; Jiang, Yi; Zhang, Yan; Gloriam, David E.; Xu, H. Eric

doi:10.1016/j.molcel.2022.05.031

Cited by 55 publications

(50 citation statements)

References 82 publications

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“…5-HT4, 5-HT6 and 5-HT7 with G s , and 5-HT4 with G i1 ) confirmed the role of TM5 and TM6, and in particular their variable length, as a selectivity filter for G-protein binding 26 . The authors also showed via bioinformatics analysis that this macro-switch is conserved among other class A GPCRs 26 . Yet, a comprehensive pictures of the structural hallmarks of coupling specificity remains elusive.…”

Section: Introductionsupporting

confidence: 53%

“…This notion is in line with the comparative analysis highlighting a selectivity filter operated by TM5 and TM6 (commented on 24 ). More recently, structural determination of serotonin receptors in complex with either G s or G i proteins, accompanied by a bioinformatics analysis of a representative set of class A complexes, supported the role of these secondary structure element by highlighting a macroswitch, operated by TM5 and TM6 terminals' variable length, which dictates selectivity towards G s vs G i/o 26 . Our unsupervised analysis of interface contacts entails complementary interactions between key positions on both the receptor and G-protein sides.…”

Section: Discussionmentioning

confidence: 99%

“…The recent determination of four structures of the serotonin receptors (e.g. 5-HT4, 5-HT6 and 5-HT7 with G s , and 5-HT4 with G i1 ) confirmed the role of TM5 and TM6, and in particular their variable length, as a selectivity filter for G-protein binding 26 . The authors also showed via bioinformatics analysis that this macro-switch is conserved among other class A GPCRs 26 .…”

Section: Introductionmentioning

confidence: 86%

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

Matic

Miglionico

Inoue

et al. 2022

Preprint

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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.

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Section: Introductionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 86%

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

Matic

Miglionico

Inoue

et al. 2022

Preprint

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“…However, a limitation to SBDD was the lack of a crystallographic structure for this receptor in PDB until now, thus condemning designs based on homology models. Last-minute lines of evidence [ 46 ] point to obtaining the first 5-HT 6 R crystal, which gives hope for increasing SBDD efficiency as soon as the crystallographic structure becomes available. Nevertheless, the ligand-based design has dominated the exploration of the chemical space for new 5-HT 6 R ligands so far, in which the pharmacophore model for antagonists developed by the team of Lopez-Rodriguez in 2005 seems to be the number one for the computer-aided LBDD, until now.…”

Section: 5-ht 6 R Ligands—pharmacophore Featuresmentioning

confidence: 99%

Multitargeting the Action of 5-HT6 Serotonin Receptor Ligands by Additional Modulation of Kinases in the Search for a New Therapy for Alzheimer’s Disease: Can It Work from a Molecular Point of View?

Czarnota-Łydka

Kucwaj-Brysz

Pyka

et al. 2022

IJMS

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In view of the unsatisfactory treatment of cognitive disorders, in particular Alzheimer’s disease (AD), the aim of this review was to perform a computer-aided analysis of the state of the art that will help in the search for innovative polypharmacology-based therapeutic approaches to fight against AD. Apart from 20-year unrenewed cholinesterase- or NMDA-based AD therapy, the hope of effectively treating Alzheimer’s disease has been placed on serotonin 5-HT6 receptor (5-HT6R), due to its proven, both for agonists and antagonists, beneficial procognitive effects in animal models; however, research into this treatment has so far not been successfully translated to human patients. Recent lines of evidence strongly emphasize the role of kinases, in particular microtubule affinity-regulating kinase 4 (MARK4), Rho-associated coiled-coil-containing protein kinase I/II (ROCKI/II) and cyclin-dependent kinase 5 (CDK5) in the etiology of AD, pointing to the therapeutic potential of their inhibitors not only against the symptoms, but also the causes of this disease. Thus, finding a drug that acts simultaneously on both 5-HT6R and one of those kinases will provide a potential breakthrough in AD treatment. The pharmacophore- and docking-based comprehensive literature analysis performed herein serves to answer the question of whether the design of these kind of dual agents is possible, and the conclusions turned out to be highly promising.

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“…While each GPCR binds selectively to a specific subtype of Ga subunit, how this selectivity is regulated is not fully understood. It has been reported that the length of transmembrane 5 (TM5) and TM6 is important for the selectivity of G s and G i at serotonin receptors (Huang et al, 2022). Biochemical analyses of cannabinoid and prostaglandin receptors have shown that specific amino acid residues in the inter cellular loop 2 (ICL2) contribute to their G protein selectivity (Chen et al, 2010;Sugimoto et al, 2004).…”

Section: Introductionmentioning

confidence: 99%