G
            <sub>q/11</sub>
            -dependent regulation of endosomal cAMP generation by parathyroid hormone class B GPCR

White, Anna Marie; Jean-Alphonse, Frédéric; Fang, Fei; Peña, Karina A.; Liu, Shi; König, Gabriele M.; Inoue, Asuka; Aslanoglou, Despoina; Gellman, Samuel H.; Kostenis, Evi; Xiao, Kunhong; Vilardaga, Jean Pierre

doi:10.1073/pnas.1918158117

Cited by 39 publications

(24 citation statements)

References 31 publications

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“…5b ). Notably, such observed reduction in Gq activation and βarr2 coupling to PTHR is consistent with our recent results supporting the requirement of Gq activation-dependent biosynthesis of phosphatidylinositol (3,4,5)-triphosphate for PTHR–βarrestin assembly in response to PTH 28 .…”

Section: Resultssupporting

confidence: 93%

Precise druggability of the PTH type 1 receptor

et al. 2021

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Class B G protein-coupled receptors (GPCRs) are notoriously difficult to target by small molecules because their large orthosteric peptide-binding pocket embedded deep within the transmembrane domain limits the identification and development of non-peptide small molecule ligands. Using the parathyroid hormone type 1 receptor (PTHR) as a prototypic class B GPCR target, and a combination of molecular dynamics simulations and elastic network model-based methods, we demonstrate that PTHR druggability can be effectively addressed. Here we found a key mechanical site that modulates the collective dynamics of the receptor and used this ensemble of PTHR conformers to identify selective small molecules with strong negative allosteric and biased properties for PTHR signaling in cell and PTH actions in vivo . This study provides a computational pipeline to detect precise druggable sites and identify allosteric modulators of PTHR signaling that could be extended to GPCRs to expedite discoveries of small molecules as novel therapeutic candidates.

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Section: Resultssupporting

confidence: 93%

Precise druggability of the PTH type 1 receptor

et al. 2021

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“…In the canonical model of class B1 GPCR signaling, β-arrestins terminate cAMP responses by decoupling G proteins and relocating the receptor to endosomes for degradation and ERK1/2 activation [75]. However, a shift in this paradigm occurred in recent years because a few receptors, such as PTH1R [76,77] and GLP-1R [78], can elicit endosomal cAMP production rather than promoting degradation after internalization.…”

Section: Trends In Pharmacological Sciencesmentioning

confidence: 99%

Structural perspective of class B1 GPCR signaling

Cong

Liang

Zhou

et al. 2022

Trends in Pharmacological Sciences

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Class B1 G protein-coupled receptors (GPCRs) play important roles in human physiology and disease pathology. Using cryo-electron microscopy (cryo-EM) and X-ray crystallography, the 3D structures of all 15 members of this receptor subfamily have been determined in recent years at the near-atomic level. Although they share many structural commonalities, they show distinct features in terms of ligand recognition and receptor activation. In-depth structural analyses have yielded valuable insights into the N termini of both peptide hormones and cognate receptors, the outward movement of transmembrane helix 6 (TM6), the allosteric modulation sites located in the transmembrane domain (TMD), and the constitutive signaling bias mediated by receptor splice variants. These provide new directions for the design of better therapeutic agents, thereby making these targets more druggable. Rapid advancesG protein-coupled receptors (GPCRs, see Glossary) are the most abundant membrane proteins involved in numerous physiological functions [1]. One GPCR class, the B1 or secretin family, comprises 15 receptors for peptide hormones that regulate a variety of biological processes ranging from growth and development to metabolism and neuroactivities, thereby making them important therapeutic targets for many diseases [2]. Several drugs against this class have been successfully launched to the market, and glucagon-like peptide 1 (GLP-1) and parathyroid hormone (PTH) receptor agonists have reached 'blockbuster' status [3,4]. In earlier years X-ray crystallography and nuclear magnetic resonance (NMR) structural studies on class B1 GPCRs mainly focused on the apo state and ligand-receptor complex structures (Table S1 in the supplemental material online), providing substantial information about the conformations of these receptor extracellular domains (ECDs) and transmembrane domains (TMDs), as well as about the structural basis of ligand recognition. To deepen our knowledge on the structure-activity relationship of these ligand-receptor pairs, the first two full-length structures were determined using single-particle cryo-electron microscopy (cryo-EM) in 2017 [5,6]. Since then the cryo-EM structures for all 15 members of class B1 GPCRs have been solved (Figure 1), not only giving valuable information about hormone recognition and receptor activation from a class-wide perspective but also providing a useful template for the design and development of better peptidic and/or small-molecule drugs [7][8][9][10][11][12][13][14][15][16].

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“…As illustrated in our current operational model for PTH-mediated endosomal cAMP (Fig. 4), recent observations unveil that phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5) P 3 ) is a critical determinant of PTH1R endosomal signaling by promoting recruitment of b-arrestin and the formation of a PTH1R-Gbg-barr complex (146) (Fig. 4B).…”

Section: The Role Of Lipids In Endosomal Gpcr Signalingmentioning

confidence: 65%

Structural insights into emergent signaling modes of G protein–coupled receptors

Sutkevičiūtė

Vilardaga

2020

Journal of Biological Chemistry

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G protein–coupled receptors (GPCRs) represent the largest family of cell membrane proteins, with >800 GPCRs in humans alone, and recognize highly diverse ligands, ranging from photons to large protein molecules. Very important to human medicine, GPCRs are targeted by about 35% of prescription drugs. GPCRs are characterized by a seven-transmembrane α-helical structure, transmitting extracellular signals into cells to regulate major physiological processes via heterotrimeric G proteins and β-arrestins. Initially viewed as receptors whose signaling via G proteins is delimited to the plasma membrane, it is now recognized that GPCRs signal also at various intracellular locations, and the mechanisms and (patho)physiological relevance of such signaling modes are actively investigated. The propensity of GPCRs to adopt different signaling modes is largely encoded in the structural plasticity of the receptors themselves and of their signaling complexes. Here, we review emerging modes of GPCR signaling via endosomal membranes and the physiological implications of such signaling modes. We further summarize recent structural insights into mechanisms of GPCR activation and signaling. We particularly emphasize the structural mechanisms governing the continued GPCR signaling from endosomes and the structural aspects of the GPCR resensitization mechanism, and discuss the recently uncovered and important roles of lipids in these processes.

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G _q/11 -dependent regulation of endosomal cAMP generation by parathyroid hormone class B GPCR

Cited by 39 publications

References 31 publications

Precise druggability of the PTH type 1 receptor

Precise druggability of the PTH type 1 receptor

Structural perspective of class B1 GPCR signaling

Structural insights into emergent signaling modes of G protein–coupled receptors

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G q/11 -dependent regulation of endosomal cAMP generation by parathyroid hormone class B GPCR

Cited by 39 publications

References 31 publications

Precise druggability of the PTH type 1 receptor

Precise druggability of the PTH type 1 receptor

Structural perspective of class B1 GPCR signaling

Structural insights into emergent signaling modes of G protein–coupled receptors

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G _q/11 -dependent regulation of endosomal cAMP generation by parathyroid hormone class B GPCR