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Ligands of Adrenergic Receptors: a Structural Point of View

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Ligands of Adrenergic Receptors: a Structural Point of View biomolecules Review Ligands of Adrenergic Receptors: A Structural Point of View Yiran Wu 1, Liting Zeng 1,2 and Suwen Zhao 1,2,* 1 iHuman Institute, ShanghaiTech University, Shanghai 201210, China; [email protected] (Y.W.); [email protected] (L.Z.) 2 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China * Correspondence: [email protected] 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, hypoten- sion, 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. Keywords: adrenergic receptor; adrenoreceptor; aminergic receptor; GPCR; activation mechanism; receptor–ligand interactions; selectivity; allosteric modulator; structure-based drug design 1. Introduction Adrenergic receptors (adrenoreceptors, ARs) are membrane proteins mediating the actions of epinephrine and norepinephrine. Epinephrine and norepinephrine (also called (–)-adrenaline and (–)-noradrenaline, respectively) are neurotransmitters of the sympathetic Citation: Wu, Y.; Zeng, L.; Zhao, S. nervous system and the central nervous system, and function as hormones secreted by the Ligands of Adrenergic Receptors: A adrenal medulla. There are nine members of adrenergic receptors in humans (Figure1a) , Structural Point of View. Biomolecules widely distributed throughout the body and playing key roles in many important physio- 2021, 11, 936. https://doi.org/ logical processes, such as response to stress, control of heart rate and blood pressure, and 10.3390/biom11070936 regulation of metabolism [1–3]. Besides epinephrine and norepinephrine as emergency medicines, adrenergic receptors are also the target of many medications in treatment of Academic Editor: Karsten Melcher various conditions, including hypertension, hypotension, heart failure, arrhythmias, and asthma [1,4]. In the 21st century, the development of new drugs against adrenergic re- Received: 25 May 2021 ceptors has slowed down, but the once most-neglected member β3-adrenergic receptor is Accepted: 12 June 2021 raising more attention than ever (Figure1b). Published: 24 June 2021 The adrenergic receptors belong to the rhodopsin family/class A G protein-coupled receptors (GPCRs). The β2-adrenergic receptor (β2AR) is a prototype GPCR for studies Publisher’s Note: MDPI stays neutral of sequence, structure, and function: β2AR is the first GPCR cloned [5], the second GPCR with regard to jurisdictional claims in was determined for atomic structure [6,7] (only after rhodopsin), and the first GPCR solved published maps and institutional affil- for the active state structure in a functional complex [8] (with Gs protein heterotrimer). iations. β-arrestins, the cytoplasmic partners responsible for desensitization of most GPCRs, were named after the β2AR [9,10]. Turkey β1AR has been comprehensively studied in structural biology (in this article, all structure of β1AR refers to turkey β1AR unless noted). A complex of β1AR and β-arrestin-1 was reported in 2020 [11]. Copyright: © 2021 by the authors. β2AR and β1AR are among the GPCRs with the largest numbers of structures obtained, Licensee MDPI, Basel, Switzerland. providing rich information for ligand recognition and activation mechanisms (β2AR has 38 This article is an open access article structures for 19 ligands and β1AR has 30 structures for 17 ligands). In 2019, structures of distributed under the terms and the three α2 adrenergic receptors were also reported, disclosing the structural basis for the conditions of the Creative Commons receptor-type selectivity of ligands. In this review, we summarized current achievements Attribution (CC BY) license (https:// of structural study in adrenergic receptors and advances in drug discovery based on creativecommons.org/licenses/by/ these structures. 4.0/). Biomolecules 2021, 11, 936. https://doi.org/10.3390/biom11070936 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, x 936 FOR PEER REVIEW 2 of 19 Figure 1. Adrenergic receptors as drug targets. (a) Binding affinities [12–14] of endogenous agonists in the nine adrenergic Figure 1. Adrenergic receptors as drug targets. (a) Binding affinities [12–14] of endogenous agonists in the nine adrenergic receptors. (b) Number of new drugs (approved or first marketing) for the nine adrenergic receptors in each decade. Data receptors. (b) Number of new drugs (approved or first marketing) for the nine adrenergic receptors in each decade. Data retrieved from Guide to PHARMACOLOGY [15](www.guidetopharmacology.org, accessed on 25 April 2021), GPCRdb [16] retrieved from Guide to PHARMACOLOGY [15] (www.guidetopharmacology.org, accessed on 25, April 2021), GPCRdb (gpcrdb.org, accessed on 25 April 2021), and DrugBank [17](go.drugbank.com, accessed on 25 April 2021). [16] (gpcrdb.org, accessed on 25, April 2021), and DrugBank [17] (go.drugbank.com, accessed on 25, April 2021). 2. Adrenergic Receptors in the Aminergic Receptor Subfamily 2. Adrenergic Receptors in the Aminergic Receptor Subfamily The nine adrenergic receptors in human body can be classified into three major types: The nine adrenergic receptors in human body can be classified into three major types: α1, α2, and β, each having three subtypes. Members within a major type are highly similar αin1, sequenceα2, and β, andeach function,having three but subtypes. in different Members major types within are a major distinct type in theseare highly aspects similar (see innext sequence section and for detail).function, All but the in adrenergicdifferent ma receptorsjor types belongare distinct to the in aminergic these aspects receptor (see nextsubfamily, section whichfor detail). has 42All members,the adrenergic forming receptors a single belong clade to inthe the aminergic phylogenetic receptor tree sub- of family,GPCRs which [18–21 ]has. The 42 aminergic members, receptors forming binda single monoamine clade in the neurotransmitters, phylogenetic tree acetylcholine, of GPCRs [18–21].or trace amines,The aminergic and share receptors common bind features mono inamine sequence, neurotransmitters, structure, and function acetylcholine, (Figure 2or): tracein the amines, orthosteric and siteshare (binding common site features of endogenous in sequence, ligand), structure, a conserved and function D3.32 (Ballesteros– (Figure 2): inWeinstein the orthosteric numbering, site (binding BWN [site22]) of forms endogenous a salt bridge ligand), to a theconser positivelyved D3.32 charged (Ballesteros– amino Weinsteingroup in ligand, numbering, and Y7.43 BWN and [22]) W7.40 forms stabilize a salt thisbridge salt to bridge the positively through a hydrogencharged amino bond groupand π -inπ interactionsligand, and Y7.43 (Figure and3b). W7.40 Because stabilize of the this shared salt bridge ligand through recognition a hydrogen mechanism, bond andpolypharmacology π-π interactions (drugs (Figure interacting 3b). Because with of multiplethe shared targets) ligand is recognition common inmechanism, aminergic polypharmacologyreceptors. For example, (drugs ergotamine interacting (anwith alkaloid multiple produced targets) is by common fungus) in can aminergic bind to re- 22 ceptors.aminergic For receptors example, with ergotamineKi less than (an alkaloid 1 µM[23 produced]. Other notable by fungus) cases can include bind clozapineto 22 aminer- [24] gicand receptors apomorphine with K [25i less]. Therefore, than 1 μM selectivity [23]. Other is a notable major concern cases include in drug clozapine discovery [24] against and apomorphineaminergic receptors. [25]. Therefore, selectivity is a major concern in drug discovery against aminergicThe endogenous receptors. ligands of adrenergic receptors, epinephrine and norepinephrine, are monoamineThe endogenous neurotransmitters. ligands of adrenergic Monoamine receptors, (also includeepinephrine dopamine, and norepinephrine, serotonin, and arehistamine) monoamine contains neurotransmitters. an amino group Monoamine connected to (also an aromatic include ringdopamine, by a two-carbon serotonin, chain and histamine)(Figure2b). contains When an binding amino to group receptors, connected the aromaticto an aromatic ring formsring by πa -two-carbonπ interactions chain to (FigureF6.51 and 2b). F6.52 When (Figures binding2a to and receptors,3b). Among the aromatic the monoamines, ring forms dopamineπ-π interactions is most to sim-F6.51 andilar F6.52 to epinephrine (Figures 2a and and norepinephrine 3b). Among the in monoamines, chemical structure: dopamine each is most contains similar a catechol to epi- nephrine(1,2-dihydroxybenzene) and norepinephrine group in (thus chemical collectively structure: referred each to contains as catecholamines). a catechol (1,2-dihy- The cate- cholamines are products of three successive steps in the tyrosine metabolism pathway. Their Biomolecules 2021, 11, x FOR PEER REVIEW 3 of 19 Biomolecules 2021, 11, 936 3 of 19 droxybenzene) group (thus collectively referred to as catecholamines). The catechola- mines are products of three successive steps in the tyrosine metabolism pathway. Their receptorsreceptors recognize recognize the the catechol catechol hydroxy hydroxy groups groups by by S5.42 S5.42 and
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