ReviewKeynote review: Allosterism in membrane receptors
Section snippets
GPCRs
GPCRs, which constitute the largest family of cell-surface receptors, are major targets of drugs currently in clinical use. The GPCRs display the characteristic motif of seven transmembrane helices (TMs) and thus are also referred to as 7TM receptors. The 7TM proteins account for ∼4% of the human genome. Mammalian GPCRs can be divided into three major subfamilies: class A, rhodopsin-like receptors; class B, secretin-like receptors; and class C, metabotropic glutamate-like and pheromone
Adenosine receptors
The A1 adenosine receptor (AR) was the first subtype in the AR family for which selective orthosteric and allosteric ligands were developed. The aminobenzoylthiophene derivative 2-amino-4,5-dimethyl-3-thienyl-[3-trifluoromethylphenyl]methanone (PD81723; Figure 1) was the first allosteric enhancer in the GPCR field, as originally observed by Bruns and Fergus [27]. They found that PD81723 enhances the binding of agonist radioligand [3H]cyclohexyladenosine to A1 ARs and decreases the rate of
Class B GPCRs: secretin-like receptors
Class B GPCRs (also known as the secretin-like receptor family) are a family of peptide-binding receptors comprising 15 members which share little sequence homology with class A (rhodopsin-like) or class C (mGlu) GPCRs. Several class B GPCRs, including corticotropin-releasing factor (CRF), growth hormone-releasing hormone, glucagon, secretin, calcitonin and parathyroid hormone (PTH) receptors, are crucially involved in controlling numerous important physiological processes [21].
Unlike some of
Class C GPCRs: metabotropic glutamate-like receptors
Glutamate is the major excitatory transmitter in the brain and binds to both LGICs and a family of class C GPCRs known as metabotropic glutamate receptors (mGluRs). Unlike most class A and class B GPCRs, class C GPCRs contain three domains: the extracellular Venus flytrap domain (VFD), which contains the agonist-binding site, the cysteine-rich domain (CRD) and the heptahelical domain (HD) involved in G protein activation [11]. In addition, the carboxy-terminal tail can be unusually long - for
LGICs
LGICs are membrane receptors responsible for rapid synaptic transmission and modulation of cellular activity. These channels are proteins spanning the cell membrane and forming both the binding site for the natural ligand and the ion-conducting pore, which can be opened or closed upon ligand binding. Upon activation, ion channels open to enable ion flux across the cell membrane. The flux can cause depolarization or hyperpolarization, depending on the charge and concentration of the ions.
Tyrosine kinase receptors
Tyrosine kinases are classified as transmembrane tyrosine kinase receptors (or receptor tyrosine kinases) and intracellular nonreceptor tyrosine kinases. Tyrosine kinase receptors are transmembrane proteins with a ligand-binding extracellular domain and a catalytic intracellular kinase domain. Emerging targets for cancer therapy [134], tyrosine kinase receptors have a central role in cellular growth, differentiation and oncogenesis. The activation of tyrosine kinase receptors by growth factors
Concluding remarks
Increasing evidence suggests that GPCR dimerization is common to all three classes of GPCRs. Original models describing the activation of a GPCR, especially the class A GPCRs, is generally related to the conformational change within a monomer. In the case of a dimer, it can be speculated that an orthosteric agonist for one dimerized monomer could be a positive or negative allosteric modulator for another monomer. From this point of view, most, if not all, membrane receptors could be naturally
Acknowledgements
We thank the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases for support and Srikar Rao for textual editing.
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Understanding allosteric interactions in G protein-coupled receptors using Supervised Molecular Dynamics: A prototype study analysing the human A<inf>3</inf> adenosine receptor positive allosteric modulator LUF6000
2015, Bioorganic and Medicinal ChemistryCitation Excerpt :In addition to speeding up the acquisition of the ligand–receptor recognition trajectory, this approach facilitates the identification and the structural characterization of multiple binding events (such as meta-binding, allosteric, and orthosteric sites) by taking advantage of the all-atom MD simulations accuracy of GPCR–ligand complexes embedded into explicit lipid–water environment.5 Interestingly, adenosine receptors (ARs) were among the first GPCRs discovered to be allosterically regulated and, in particular, allosteric enhancers for A1 and A3 ARs have been widely investigated.1,2,6 Among the most interesting allosteric enhancers for the A3 AR, N-(3,4-dichlorophenyl)-2-cyclohexyl-1H-imidazo[4,5-c]quinolin-4-amine (LUF6000, see Fig. 1) has been deeply characterized.7,8
Osteoblast differentiation and survival: A role for A<inf>2B</inf> adenosine receptor allosteric modulators
2014, Biochimica et Biophysica Acta - Molecular Cell ResearchCitation Excerpt :In the perspective of a systemic use of an orthosteric agonist of A2B AR, the wide distribution of ARs throughout the body would increase the risk of adverse effects. For this reason, in the last years the development of allosteric modulators of ARs has represented an area of active research [14,15]. Indeed, these compounds may represent a more “physiologic” alternative to orthosteric ligands thanks to their capability of modulating the interaction between the receptor and its endogenous ligands.
The role of a sodium ion binding site in the allosteric modulation of the A<inf>2A</inf> adenosine G protein-coupled receptor
2013, StructureCitation Excerpt :Thus, molecules targeting other (allosteric) sites can modulate binding of native orthosteric ligands and shift the delicate equilibrium between active and inactive states of GPCRs (Christopoulos, 2002). Potential therapeutic advantages include a gain in target selectivity, the “ceiling effect,” and preservation of the spatiotemporal profile of intercellular signaling (Conn et al., 2009; Gao and Jacobson, 2006; Göblyös and Ijzerman, 2011; Jacobson et al., 2011). Some endogenous chemical entities, such as ions or lipids, have also been demonstrated to act as allosteric modulators of GPCRs (Christopoulos, 2002; Gao and Ijzerman, 2000; Neve et al., 2001), but the structural basis and functional importance of these interactions are not well understood.
Allosteric modulation and functional selectivity of G protein-coupled receptors
2013, Drug Discovery Today: TechnologiesConsideration of allosterism and interacting proteins in the physiological functions of the serotonin transporter
2012, Biochemical PharmacologyDiversity and modularity of G protein-coupled receptor structures
2012, Trends in Pharmacological SciencesCitation Excerpt :Precise 3D structural knowledge of the EC regions is of great value in GPCR drug discovery because the N-terminus and/or ECLs play major roles in subtype selectivity for both peptide and small-molecule ligands. This 3D knowledge is even more crucial for understanding the binding and mechanisms of action for allosteric modulators and ‘bitopic’ ligands of GPCRs [6,32–34] because these promising new classes of therapeutic compounds often specifically target the loop regions of receptors. As expected from the characteristic 7TM sequence pattern and early 3D modeling, crystal structures confirm the overall structural conservation of the 7TM helical bundle, with Cα root mean squared deviations (RMSD) of <3 Å in TM-helices between any pairs of GPCRs.
Allosteric modulators could be especially valuable in controlling receptors for which the design of orthosteric agonists or antagonists has been elusive.
- 1
Zhan-Guo Gao Zhan-Guo Gao is a Staff Scientist in the Molecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK, NIH. After studying medicine, he became interested in the mechanisms of action of G-protein-coupled receptors. Both his current field of research and his PhD thesis work at the Leiden-Amsterdam Centre for Drug Research in The Netherlands concern adenosine receptors. He has published extensively on allosteric modulation of adenosine receptors.
- 2
Kenneth A. Jacobson Kenneth Jacobson is Chief of the Molecular Recognition Section of the Laboratory of Bioorganic Chemistry, NIDDK, NIH. He is a medicinal chemist with a research focus on receptors for nucleosides and nucleotides. Jacobson completed his PhD studies at the University of California, San Diego, USA, in 1981 and subsequent postdoctoral work at the Weizmann Institute of Science, Rehovot, Israel. He recently served as Chair of the Medicinal Chemistry Division of the American Chemical Society. He is a ‘highly cited researcher’ in Pharmacology and Toxicology (Institute for Scientific Information) and received the first Giuliana Fassina Award from the Purine Club in 1996, as well as the Hillebrand Prize of the Chemical Society of Washington in 2003 for ‘outstanding research contributions in the medicinal chemistry of G-protein-coupled receptors’.