Lighting up multiprotein complexes: lessons from GPCR oligomerization

Spatiotemporal characterization of protein protein interactions (PPIs) is essential in determining the molecular mechanisms of intracellular signaling processes. In this review, we discuss how new methodological strategies derived from non-invasive fluorescence- and luminescence-based approaches (FRET, BRET, BiFC and BiLC), when applied to the study of G protein-coupled receptor (GPCR) oligomerization, can be used to detect specific PPIs in live cells. These technologies alone or in concert with complementary methods (SRET, BRET or BiFC, and SNAP-tag or TR-FRET) can be extremely powerful approaches for PPI visualization, even between more than two proteins. Here we provide a comprehensive update on all the biotechnological aspects, including the strengths and weaknesses, of new fluorescence- and luminescence-based methodologies, with a specific focus on their application for studying PPIs

On the expanding terminology in the GPCR field: The meaning of receptor mosaics and receptor heteromers

The oligomerization of G protein-coupled receptors (GPCRs) is a fact that deserves further attention as increases both the complexity and diversity of the receptor-mediated signal transduction, thus enriching the cell signaling. Consequently, in the present review we tackle among others the problems concerning the terminology used to describe aspects surrounding the GPCRs oligomerization phenomenon. Therefore, the theoretical implications of the GPCR oligomerization will be briefly discussed together with possible implications of this phenomenon especially for new strategies in drug development

Parathyroid hormone receptors in GtoPdb v.2021.3

The parathyroid hormone receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Parathyroid Hormone Receptors [49]) are class B G protein-coupled receptors. The parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor (PTH1 receptor) is activated by precursor-derived peptides: PTH (84 amino acids), and PTHrP (141 amino-acids) and related peptides (PTH-(1-34), PTHrP-(1-36)). The parathyroid hormone 2 receptor (PTH2 receptor) is activated by the precursor-derived peptide TIP39 (39 amino acids). [125I]PTH may be used to label both PTH1 and PTH2 receptors. The structure of a long-active PTH analogue (LA-PTH, an hybrid of PTH-(1-13) and PTHrP-(14-36)) bound to the PTH1 receptor-Gs complex has been resolved by cryo-electron microscopy [147]. Another structure of a PTH-(1-34) analog bound to a thermostabilized inactive PTH1 receptor has been obtained with X-ray crytallography [34]

Parathyroid hormone receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The parathyroid hormone receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Parathyroid Hormone Receptors [47]) are family B G protein-coupled receptors. The parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor (PTH1 receptor) is activated by precursor-derived peptides: PTH (84 amino acids), and PTHrP (141 amino-acids) and related peptides (PTH-(1-34), PTHrP-(1-36)). The parathyroid hormone 2 receptor (PTH2 receptor) is activated by the precursor-derived peptide TIP39 (39 amino acids). [125I]PTH may be used to label both PTH1 and PTH2 receptors

Parathyroid hormone receptors in GtoPdb v.2023.1

The parathyroid hormone receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Parathyroid Hormone Receptors [50]) are class B G protein-coupled receptors. The parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor (PTH1 receptor) is activated by precursor-derived peptides: PTH (84 amino acids), and PTHrP (141 amino-acids) and related peptides (PTH-(1-34), PTHrP-(1-36)). The parathyroid hormone 2 receptor (PTH2 receptor) is activated by the precursor-derived peptide TIP39 (39 amino acids). [125I]PTH may be used to label both PTH1 and PTH2 receptors. The structure of a long-active PTH analogue (LA-PTH, an hybrid of PTH-(1-13) and PTHrP-(14-36)) bound to the PTH1 receptor-Gs complex has been resolved by cryo-electron microscopy [148]. Another structure of a PTH-(1-34) analog bound to a thermostabilized inactive PTH1 receptor has been obtained with X-ray crytallography [35]

THE CONCISE GUIDE TO PHARMACOLOGY 2019/20 : G protein- coupled receptors

The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14748. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.Peer reviewe

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate

The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors.

peer reviewedThe Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.16177. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate

Precise druggability of the PTH type 1 receptor

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