GPCRs

Structure, Function, and Drug Discovery

Beata Jastrzebska,Paul S.-H. Park

• Publisher: Academic Press
• Year: 2019
• ISBN:
  9780128167281
• Topic: Scienze biologiche
• Subtopic: Biofisica

GPCRS: Structure, Function, and Drug Discovery provides a comprehensive overview of recent discoveries and our current understanding of GPCR structure, signaling, physiology, pharmacology and methods of study. In addition to the fundamental aspects of GPCR function and dynamics, international experts discuss crystal structures, GPCR complexes with partner proteins, GPCR allosteric modulation, biased signaling through protein partners, deorphanization of GPCRs, and novel GPCR-targeting ligands that could lead to the development of new therapeutics against human diseases. GPCR association with, and possible therapeutic pathways for, retinal degenerative diseases, Alzheimer's disease, Parkinson's disease, cancer and diabetic nephropathy, among other illnesses, are examined in-depth.

• Addresses our current understanding and novel advances in the GPCR field, directing readers towards recent finding of key significance for translational medicine
• Combines a thorough discussion of structure and function of GPCRs with disease association and drug discovery
• Features chapter contributions from international experts in GPCR structure, signaling, physiology and pharmacology

Part I

GPCR structure

Outline

Chapter 1. Progress in GPCR structure determination

Chapter 2. Structure, function and therapeutic potential of adhesion GPCRs

Chapter 3. Structural diversity in ligand recognition by GPCRs

Chapter 4. NMR-based approaches to the study of GPCRs and GPCR-ligand interactions

Chapter 5. Supramolecular structure of opsins

Chapter 6. Molecular determinants of GPCR oligomerization

Chapter 7. Structure of G-protein-coupled receptor heteromers

Chapter 8. Class A GPCR oligomerization: reasons of controversy

Chapter 1

Progress in GPCR structure determination

Xiangli Qu ^{1 , 2 , 3 , a} , Dejian Wang ^{1 , 2 , 3 , a} , and Beili Wu ^{1 , 3 , 4 , 5 1} CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Pudong, Shanghai, China ² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Pudong, Shanghai, China ³ University of Chinese Academy of Sciences, Beijing, China ⁴ School of Life Science and Technology, ShanghaiTech University, Pudong, Shanghai, China ⁵ CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing, China

Abstract

G protein-coupled receptors (GPCRs) are widely distributed in the human body and trigger cellular responses to a variety of extracellular stimuli. The diverse functions of GPCRs make these receptors key players in numerous physiological regulations and valuable drug targets for many diseases. The GPCR structures are important for understanding the molecular mechanisms of GPCR signaling and enable structure-based drug discovery. Recent advances in GPCR structure determination have provided valuable insights into ligand recognition, receptor activation, and signaling transduction of these receptors. Here we summarize the recent progress, techniques, and discoveries in GPCR structural studies to elucidate the successful strategies for GPCR structure determination and structural basis of GPCR function.

Keywords

Drug discovery; G protein-coupled receptor (GPCR); Ligand recognition; Signal transduction; Structure determination

1.1. Introduction

GPCRs constitute the largest superfamily of cell membrane receptors and are distributed in almost all the human tissues and organs. Involved in numerous physiological and pathological regulations, these receptors sense the outside stimuli and convey the extracellular information into cells, and ultimately result in subsequent cellular responses, playing important roles in maintaining the function of the human body (Rosenbaum et al., 2009). These regulation processes are achieved through the coordination between ligands, GPCRs, effector proteins (G proteins, arrestins, etc.) and downstream signaling pathways. Upon binding to the ligands, GPCRs exhibit conformational changes, which lead to the recruitment and activation of specific effector proteins and trigger the modulation of downstream signaling pathways. The biological complexity and importance of the GPCR network make these receptors key modulators of various pathological processes and valuable drug targets for many diseases. Structural studies of GPCRs have experienced tremendous progress in the last two decades. The emergence of the newly solved GPCR structures not only illustrates the molecular mechanisms of ligand recognition, receptor activation, and signaling transduction, but also provides the structural basis for drug development.

1.1.1. GPCR classification and function

More than 800 individual human GPCRs have been identified so far, accounting for 4% of entire human protein-coding genome (Foord et al., 2005). Based on phylogenetic sequence analysis and structure similarities, GPCRs are classified into five main families named rhodopsin (class A), secretin (class B1), adhesion (class B2), glutamate (class C), and frizzled/taste2 (class F) (Fredriksson et al., 2003).

All GPCRs share the same structural architecture composed of an extracellular N terminus, an intracellular C terminus, and a transmembrane heptahelical bundle (TM1-7) connected by extracellular loops (ECLs) and intracellular loops (ICLs) (Fig. 1.1). The class A GPCR family, which has the largest number of receptors, is the most investigated GPCR family and has relatively simple structure composition with a short N terminus. Compared to the class A receptors, the class B1 GPCRs contain a longer N terminal extracellular domain (ECD) and a transmembrane domain (TMD), together to bind to peptide hormones that are important for Ca²⁺ homeostasis and blood glucose regulation (Culhane et al., 2015). The adhesion GPCRs are characterized by an extremely large N terminus consisting of various adhesion domains and an autoproteolysis domain that undergoes self-cleavage during receptor maturation (Hamann et al., 2015). The class C GPCR family predominantly includes the metabotropic glutamate receptors (mGluRs) and taste receptors. A distinguishing feature of glutamate GPCRs is to form constitutive homodimers or heterodimers mediated by a large N terminus that contains a venus flytrap domain (VFTD) and a cysteine-rich domain (CRD) (Rondard et al., 2011). Viewed as a noncanonical group in the GPCR superfamily, the class F GPCR family consists of 10 Frizzleds (FZDs) and Smoothened (SMO), and exhibits a similar structure architecture comprising a TMD and a CRD at the N terminus (Huang and Klein, 2004).

Figure 1.1 Cartoon models displaying structural features of GPCRs from different classes. The canonical transmembrane heptahelical bundle structure is shared by all GPCRs. Class A GPCRs possess a relatively short N terminus, while an ECD is shown in class B1 GPCRs to accommodate hormone peptide binding with the TMD. The extremely large N terminus of class B2 GPCRs consists of several cell adhesion domains and a GAIN domain, which contains a conserved GPS motif associated with autoproteolysis. Responsible for endogenous ligand binding and dimer formation, the VFTD in class C GPCRs is connected to the TMD through a flexible CRD linker. Class F GPCRs are characterized by a CRD at the N terminus followed by an LD and TMD.

Diverse in structure and function, GPCRs mediate most cellular responses to ions, photons, hormones, neurotransmitters, pheromones, odors, lipids, and large proteins. Due to their abundance and significant roles in signal transduction and cellular regulation, GPCRs participate in the regulation of a variety of physiological functions, such as smell, taste, vision, secretion, metabolism, nerve system regulation, immune response, cellular differentiation, and embryonic development. Consequently, the malfunction of GPCRs results in many diseases, such as diabetes, obesity, cardiovascular disease, neurodegenerative disorders, inflammation, and cancer (Hu et al., 2017), making these receptors important drug targets.

1.1.2. GPCR structure and drug discovery

An easy and direct interaction access between GPCRs and therapeutics is provided due to their localization on the cell surface instead of in the cytoplasm. Over 30% of marketed drugs target GPCRs (RASK-Andersen et al., 2011) and great efforts are under way to generate new lead compounds. The newly emerged atomic structures of different GPCRs in complex with various ligands provide valuable insights into the ligand recognition mechanisms of these receptors, broadening the way and accelerating the pace for structure-based drug discovery. Structure-based drug design is applied to rational and efficient disc...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Preface
• Part I. GPCR structure
• Part II. GPCR function
• Part III. GPCRs in disease and targeted drug discovery
• Index