Dissecting the structural features of β-arrestins as multifunctional proteins

Yun, Yaejin; Ji, Jeongseok; Lee, Hyung Ho

doi:10.1016/j.bbapap.2021.140603

Cited by 5 publications

(4 citation statements)

References 154 publications

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“…The G protein-GPCR complexes (PDB, entry codes: 6CMO, 6FUF, 6OYA, 6OS9, 7L0P, 7JJO, 6OIK) (Table S1) [30][31][32][33][34][35][36], Arrestin-GPCR complexes (PDB, entry codes: 4ZWJ, 5DGY, 5W0P, 6PWC, 6UP7, 6TKO, 6U1N) (Table S2) and inactive GPCRs (PDB, entry codes: 1U19, 6Z66, 7BVQ, 3UON) (Table S3) were obtained from the Protein Data Bank (PDB) [37][38][39][40][41][42][43][44][45][46][47][48]. Among them, four types of receptors, Rhodopsin, M 2 R, β 1 AR and NTSR1 were included to investigate the performance of the active states of G protein-related system and Arrestin-associated mode, which are closely associated with signaling pathways involved in GPCR activation [49][50][51].…”

Section: Protein Structure Preparationmentioning

confidence: 99%

Computational Investigation of Functional Water Molecules Upon GPCR Bound to G protein or Arrestin

Sun²,

Kang

et al. 2022

Preprint

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G protein-coupled receptors (GPCRs) are membrane proteins, which constitutes the largest family of drug targets. The activated GPCR can bound either G protein or Arrestin to accomplish its activation. Water molecules were reported to play an intriguing role in GPCR activation. Nevertheless, reported studies are focused in the hydrophobic helical bundle region. How water molecules function upon GPCR bound either G protein or Arrestin is rarely studied. To address this issue, we carried out computational studies on water molecules in both GPCR/G protein complexes and GPCR/Arrestin complexes. Using the inhomogeneous fluid theory (IFT), hydration sites of GPCRs in G protein or Arrestin binding state were located and their functions were comprehensively analyzed. In the interaction surface of GPCR-G protein/Arrestin, a lot of water molecules were found. In addition, we found that the number of water molecules on the interaction surface of GPCR-G protein/Arrestin system is highly associated with the insertion depth of the α5-helix and “Finger Loop”. We observed that water molecules near the interaction surface of GPCR-G protein/Arrestin exhibit great differences. Most G protein-related structures attract more function water molecules than Arrestin-associated structures. The G protein-related GPCRs show more potent binding water molecules and water-mediated hydrogen-bond compared to Arrestin complexes. Moreover, a small amount of water molecules is observed in the NPxxY region, while a large number of water molecules are in the orthosteric pocket and form rich interaction networks. Our results provide a comprehensive and deep understanding on the hydration sites in GPCRs and may have important implications for GPCR-targeted drug design with functional selectivity.

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Section: Protein Structure Preparationmentioning

confidence: 99%

Computational Investigation of Functional Water Molecules Upon GPCR Bound to G protein or Arrestin

Sun²,

Kang

et al. 2022

Preprint

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“…However, an even more subtle but intriguing mode of signaling has been attributed to the ability of a receptor to activate signaling pathways independent of G-protein activation. This occurs through the scaffolding of signaling complexes by β-arrestin, a component of the GPCR desensitization and internalization machinery. , The process by which ligands differentially modulate G-protein-dependent and/or G-protein-independent (β-arrestin) pathways to mediate specific downstream signal transduction routes is a phenomenon known as functional selectivity or biased agonism …”

Section: Introductionmentioning

confidence: 99%

“…This occurs through the scaffolding of signaling complexes by β-arrestin, a component of the GPCR desensitization and internalization machinery. 5,6 The process by which ligands differentially modulate G-protein-dependent and/or G-protein-independent (β-arrestin) pathways to mediate specific downstream signal transduction routes is a phenomenon known as functional selectivity or biased agonism. 3 The concept of biased agonism has progressively reshaped our understanding of GPCR signaling and shifted the paradigm of GPCR drug discovery.…”

Section: ■ Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Potent and Subtype-Selective Dopamine D₂ Receptor Biased Partial Agonists Discovered via an Ugi-Based Approach

et al. 2021

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Using a previously unexplored, efficient, and versatile multicomponent method, we herein report the rapid generation of novel potent and subtype-selective DRD 2 biased partial agonists. This strategy exemplifies the search for diverse and previously unexplored moieties for the secondary/allosteric pharmacophore of the common phenyl-piperazine scaffold. The pharmacological characterization of the new compound series led to the identification of several ligands with excellent DRD 2 affinity and subtype selectivity and remarkable functional selectivity for either the cAMP (22a and 24d) or the β-arrestin (27a and 29c) signaling pathways. These results were further interpreted on the basis of molecular models of these ligands in complex with the recent DRD 2 crystal structures, highlighting the critical role of the secondary/allosteric pharmacophore in modulating the functional selectivity profile.

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Computational investigation of functional water molecules in GPCRs bound to G protein or arrestin

Sun²,

Kang³

et al. 2022

J Comput Aided Mol Des

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Dissecting the structural features of β-arrestins as multifunctional proteins

Cited by 5 publications

References 154 publications

Computational Investigation of Functional Water Molecules Upon GPCR Bound to G protein or Arrestin

Computational Investigation of Functional Water Molecules Upon GPCR Bound to G protein or Arrestin

Potent and Subtype-Selective Dopamine D₂ Receptor Biased Partial Agonists Discovered via an Ugi-Based Approach

Computational investigation of functional water molecules in GPCRs bound to G protein or arrestin

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Dissecting the structural features of β-arrestins as multifunctional proteins

Cited by 5 publications

References 154 publications

Computational Investigation of Functional Water Molecules Upon GPCR Bound to G protein or Arrestin

Computational Investigation of Functional Water Molecules Upon GPCR Bound to G protein or Arrestin

Potent and Subtype-Selective Dopamine D2 Receptor Biased Partial Agonists Discovered via an Ugi-Based Approach

Computational investigation of functional water molecules in GPCRs bound to G protein or arrestin

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Product

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Potent and Subtype-Selective Dopamine D₂ Receptor Biased Partial Agonists Discovered via an Ugi-Based Approach