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Biomolecules
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GPCRs: Structure, Biology and Potential Applications
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GPCRs: Structure, Biology and Potential Applications

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (15 April 2021) | Viewed by 34080

Special Issue Editor

Prof. Dr. Karsten Melcher

grade E-Mail Website
Guest Editor
Center for Cancer and Cell Biology, Structural Biology Program, Van Andel Research Institute, 333 Bostwick Avenue Northeast, Grand Rapids, MI 49503, USA
Interests: structural biology with a special emphasis on AMPK; Jasmonate/plant hormone signaling; GPCRs

Special Issue Information

Dear Colleagues,

The more than 800 human GPCRs impact almost all aspects of physiology and represent the largest family of drug targets. The recent revolution in the structural biology of GPCRs in complexes with agonists, antagonists, allosteric modulators, and intracellular signaling partners has been crucial in determining a general mechanism of GPCR activation and has provided structural frameworks for the rational design of pharmacological GPCR regulators.

For this Special Issue, we would like to invite review articles by leading experts on the structure–function relationship of select GPCRs and GPCR subfamilies, GPCRs as therapeutics, and the coupling of GPCRs to G proteins, arrestins, and GRKs.

Prof. Dr. Karsten Melcher
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • GPCR
  • medicinal chemistry
  • G proteins
  • arrestins
  • GPCR kinases
  • X-ray crystallography
  • Cryo-EM
  • computational drug discovery

Published Papers (6 papers)

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Research

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16 pages, 2995 KiB  
Article
Integrated Multi-Class Classification and Prediction of GPCR Allosteric Modulators by Machine Learning Intelligence
by Tianling Hou, Yuemin Bian, Terence McGuire and Xiang-Qun Xie
Biomolecules 2021, 11(6), 870; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11060870 - 11 Jun 2021
Cited by 13 | Viewed by 4344
Abstract
G-protein-coupled receptors (GPCRs) are the largest and most diverse group of cell surface receptors that respond to various extracellular signals. The allosteric modulation of GPCRs has emerged in recent years as a promising approach for developing target-selective therapies. Moreover, the discovery of new [...] Read more.
G-protein-coupled receptors (GPCRs) are the largest and most diverse group of cell surface receptors that respond to various extracellular signals. The allosteric modulation of GPCRs has emerged in recent years as a promising approach for developing target-selective therapies. Moreover, the discovery of new GPCR allosteric modulators can greatly benefit the further understanding of GPCR cell signaling mechanisms. It is critical but also challenging to make an accurate distinction of modulators for different GPCR groups in an efficient and effective manner. In this study, we focus on an 11-class classification task with 10 GPCR subtype classes and a random compounds class. We used a dataset containing 34,434 compounds with allosteric modulators collected from classical GPCR families A, B, and C, as well as random drug-like compounds. Six types of machine learning models, including support vector machine, naïve Bayes, decision tree, random forest, logistic regression, and multilayer perceptron, were trained using different combinations of features including molecular descriptors, Atom-pair fingerprints, MACCS fingerprints, and ECFP6 fingerprints. The performances of trained machine learning models with different feature combinations were closely investigated and discussed. To the best of our knowledge, this is the first work on the multi-class classification of GPCR allosteric modulators. We believe that the classification models developed in this study can be used as simple and accurate tools for the discovery and development of GPCR allosteric modulators. Full article
(This article belongs to the Special Issue GPCRs: Structure, Biology and Potential Applications)
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19 pages, 3911 KiB  
Article
The Open Question of How GPCRs Interact with GPCR Kinases (GRKs)
by M. Claire Cato, Yu-Chen Yen, Charnelle J. Francis, Kaely E. Elkins, Afzaal Shareef, Rachel Sterne-Marr and John J. G. Tesmer
Biomolecules 2021, 11(3), 447; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11030447 - 17 Mar 2021
Cited by 10 | Viewed by 3781
Abstract
G protein-coupled receptors (GPCRs), which regulate a vast number of eukaryotic processes, are desensitized by various mechanisms but, most importantly, by the GPCR kinases (GRKs). Ever since GRKs were first identified, investigators have sought to determine which structural features of GRKs are used [...] Read more.
G protein-coupled receptors (GPCRs), which regulate a vast number of eukaryotic processes, are desensitized by various mechanisms but, most importantly, by the GPCR kinases (GRKs). Ever since GRKs were first identified, investigators have sought to determine which structural features of GRKs are used to select for the agonist-bound states of GPCRs and how this binding event in turn enhances GRK catalytic activity. Despite a wealth of molecular information from high-resolution crystal structures of GRKs, the mechanisms driving activation have remained elusive, in part because the GRK N-terminus and active site tether region, previously proposed to serve as a receptor docking site and to be key to kinase domain closure, are often disordered or adopt inconsistent conformations. However, two recent studies have implicated other regions of GRKs as being involved in direct interactions with active GPCRs. Atomic resolution structures of GPCR–GRK complexes would help refine these models but are, so far, lacking. Here, we assess three distinct models for how GRKs recognize activated GPCRs, discuss limitations in the approaches used to generate them, and then experimentally test a hypothetical GPCR interaction site in GRK2 suggested by the two newest models. Full article
(This article belongs to the Special Issue GPCRs: Structure, Biology and Potential Applications)
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Review

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28 pages, 2663 KiB  
Review
Alternative Pre-mRNA Splicing of the Mu Opioid Receptor Gene, OPRM1: Insight into Complex Mu Opioid Actions
by Shan Liu, Wen-Jia Kang, Anna Abrimian, Jin Xu, Luca Cartegni, Susruta Majumdar, Patrick Hesketh, Alex Bekker and Ying-Xian Pan
Biomolecules 2021, 11(10), 1525; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11101525 - 15 Oct 2021
Cited by 12 | Viewed by 3457
Abstract
Most opioid analgesics used clinically, including morphine and fentanyl, as well as the recreational drug heroin, act primarily through the mu opioid receptor, a class A Rhodopsin-like G protein-coupled receptor (GPCR). The single-copy mu opioid receptor gene, OPRM1, undergoes extensive alternative splicing, [...] Read more.
Most opioid analgesics used clinically, including morphine and fentanyl, as well as the recreational drug heroin, act primarily through the mu opioid receptor, a class A Rhodopsin-like G protein-coupled receptor (GPCR). The single-copy mu opioid receptor gene, OPRM1, undergoes extensive alternative splicing, creating multiple splice variants or isoforms via a variety of alternative splicing events. These OPRM1 splice variants can be categorized into three major types based on the receptor structure: (1) full-length 7 transmembrane (TM) C-terminal variants; (2) truncated 6TM variants; and (3) single TM variants. Increasing evidence suggests that these OPRM1 splice variants are pharmacologically important in mediating the distinct actions of various mu opioids. More importantly, the OPRM1 variants can be targeted for development of novel opioid analgesics that are potent against multiple types of pain, but devoid of many side-effects associated with traditional opiates. In this review, we provide an overview of OPRM1 alternative splicing and its functional relevance in opioid pharmacology. Full article
(This article belongs to the Special Issue GPCRs: Structure, Biology and Potential Applications)
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19 pages, 4800 KiB  
Review
Ligands of Adrenergic Receptors: A Structural Point of View
by Yiran Wu, Liting Zeng and Suwen Zhao
Biomolecules 2021, 11(7), 936; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11070936 - 24 Jun 2021
Cited by 40 | Viewed by 11278
Abstract
Adrenergic receptors are G protein-coupled receptors for epinephrine and norepinephrine. They are targets of many drugs for various conditions, including treatment of hypertension, hypotension, and asthma. Adrenergic receptors are intensively studied in structural biology, displayed for binding poses of different types of ligands. [...] Read more.
Adrenergic receptors are G protein-coupled receptors for epinephrine and norepinephrine. They are targets of many drugs for various conditions, including treatment of hypertension, hypotension, and asthma. Adrenergic receptors are intensively studied in structural biology, displayed for binding poses of different types of ligands. Here, we summarized molecular mechanisms of ligand recognition and receptor activation exhibited by structure. We also reviewed recent advances in structure-based ligand discovery against adrenergic receptors. Full article
(This article belongs to the Special Issue GPCRs: Structure, Biology and Potential Applications)
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21 pages, 1770 KiB  
Review
DEER Analysis of GPCR Conformational Heterogeneity
by Matthias Elgeti and Wayne L. Hubbell
Biomolecules 2021, 11(6), 778; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11060778 - 22 May 2021
Cited by 21 | Viewed by 4750
Abstract
G protein-coupled receptors (GPCRs) represent a large class of transmembrane helical proteins which are involved in numerous physiological signaling pathways and therefore represent crucial pharmacological targets. GPCR function and the action of therapeutic molecules are defined by only a few parameters, including receptor [...] Read more.
G protein-coupled receptors (GPCRs) represent a large class of transmembrane helical proteins which are involved in numerous physiological signaling pathways and therefore represent crucial pharmacological targets. GPCR function and the action of therapeutic molecules are defined by only a few parameters, including receptor basal activity, ligand affinity, intrinsic efficacy and signal bias. These parameters are encoded in characteristic receptor conformations existing in equilibrium and their populations, which are thus of paramount interest for the understanding of receptor (mal-)functions and rational design of improved therapeutics. To this end, the combination of site-directed spin labeling and EPR spectroscopy, in particular double electron–electron resonance (DEER), is exceedingly valuable as it has access to sub-Angstrom spatial resolution and provides a detailed picture of the number and populations of conformations in equilibrium. This review gives an overview of existing DEER studies on GPCRs with a focus on the delineation of structure/function frameworks, highlighting recent developments in data analysis and visualization. We introduce “conformational efficacy” as a parameter to describe ligand-specific shifts in the conformational equilibrium, taking into account the loose coupling between receptor segments observed for different GPCRs using DEER. Full article
(This article belongs to the Special Issue GPCRs: Structure, Biology and Potential Applications)
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25 pages, 8237 KiB  
Review
Receptor-Arrestin Interactions: The GPCR Perspective
by Mohammad Seyedabadi, Mehdi Gharghabi, Eugenia V. Gurevich and Vsevolod V. Gurevich
Biomolecules 2021, 11(2), 218; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11020218 - 4 Feb 2021
Cited by 41 | Viewed by 5589
Abstract
Arrestins are a small family of four proteins in most vertebrates that bind hundreds of different G protein-coupled receptors (GPCRs). Arrestin binding to a GPCR has at least three functions: precluding further receptor coupling to G proteins, facilitating receptor internalization, and initiating distinct [...] Read more.
Arrestins are a small family of four proteins in most vertebrates that bind hundreds of different G protein-coupled receptors (GPCRs). Arrestin binding to a GPCR has at least three functions: precluding further receptor coupling to G proteins, facilitating receptor internalization, and initiating distinct arrestin-mediated signaling. The molecular mechanism of arrestin–GPCR interactions has been extensively studied and discussed from the “arrestin perspective”, focusing on the roles of arrestin elements in receptor binding. Here, we discuss this phenomenon from the “receptor perspective”, focusing on the receptor elements involved in arrestin binding and emphasizing existing gaps in our knowledge that need to be filled. It is vitally important to understand the role of receptor elements in arrestin activation and how the interaction of each of these elements with arrestin contributes to the latter’s transition to the high-affinity binding state. A more precise knowledge of the molecular mechanisms of arrestin activation is needed to enable the construction of arrestin mutants with desired functional characteristics. Full article
(This article belongs to the Special Issue GPCRs: Structure, Biology and Potential Applications)
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