Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure

Liu, Xiangyu; Ahn, Seungkirl; Kahsai, Alem W.; Meng, Kai-Cheng; Latorraca, Naomi R.; Pani, Biswaranjan; Venkatakrishnan, AJ; Masoudi, Ali; Weis, William I.; Dror, Ron O.; Chen, Xin; Lefkowitz, Robert J.; Kobilka, Brian K.

doi:10.1038/nature23652

Cited by 172 publications

(184 citation statements)

References 39 publications

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“…The presence of energetically stable meta‐binding sites, alternative to the canonical orthosteric one, could open the scenario in which a ligand can simultaneously recognize the same receptor with a stoichiometry other than 1 : 1. In recent crystallographic structures, class A GPCRs contemporary bound orthosteric and allosteric ligands . Moreover, the development of dualsteric agents corroborates this intriguing scenario.…”

Section: Introductionmentioning

confidence: 84%

Could Adenosine Recognize its Receptors with a Stoichiometry Other than 1 : 1?

Deganutti

Salmaso

Moro

2018

Molecular Informatics

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One of the most largely accepted concepts in the G protein-coupled receptors (GPCRs) field is that the ligand, either agonist or antagonist, recognizes its receptor with a stoichiometry of 1 : 1. Recent experimental evidence, reporting ternary complexes formed by GPCR:orthosteric: allosteric ligands, has complicated the ligand-receptor 1 : 1 binding scenario. Molecular modeling simulations have been used to retrieve insights on the whole ligand-receptor recognition process, beyond information on the final bound state provided by experimental techniques. The simulation of adenosine binding pathways towards the A adenosine receptor highlighted the presence of alternative binding sites (meta-binding sites) beside the canonical orthosteric one, mainly in proximity to the extracellular vestibule. In light of all these considerations, we investigated the possibility that a second molecule of adenosine engages its receptor when this is already in the holo form, generating a ternary complex with a stoichiometry of 2 : 1. Unexpectedly, supervised molecular dynamics (SuMD) simulations showed that the A adenosine receptor could bind the second molecule of adenosine in one of the possible meta-binding sites as well as into its orthosteric site. The formation of this ternary complex, which favored the formation of the intracellular "ionic lock" between R102 (3.50) and E228 (6.30), could putatively be framed in the context of a negative allosteric regulation.

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Section: Introductionmentioning

confidence: 84%

Could Adenosine Recognize its Receptors with a Stoichiometry Other than 1 : 1?

Deganutti

Salmaso

Moro

2018

Molecular Informatics

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“…EP2 is an integral membrane protein that has an extracellular N-terminus and an intracellular c-terminus (18,19). It has seven transmembrane (7-TM) α-helices (TM-1 to TM-7) connected by three intracellular (IL-1 to IL-3) and three extracellular (EL-1 to EL-3) loops (20). The EP2 is bound to a heterotrimeric G protein complex consisting of the G stimulatory (G sub. )…”

Section: Structure Of the Ep2 Receptormentioning

confidence: 99%

Prostaglandin EP2 receptor: Novel therapeutic target for human cancers (Review)

Sun

2018

Int J Mol Med

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Prostaglandin E2 (PGE2) receptor 2 subtype (EP2), which is a metabolite of arachidonic acid that binds with and regulates cellular responses to PGE2, is associated with numerous physiological and pathological events in a wide range of tissues. As a stimulatory G protein‑coupled receptor, PGE2‑induced EP2 activation can activate adenylate cyclase, leading to increased cytoplasmic cAMP levels and activation of protein kinase A. The EP2 receptor can also activate the glycogen synthase kinase 3β and β‑catenin pathways. The present study aimed to review the roles of the EP2 receptor in tumor development, including immunity, chronic inflammation, angiogenesis, metastasis and multidrug resistance. Furthermore, the involvement of the EP2 receptor signaling pathway in cancer was discussed. Understanding the role and mechanisms of action of the EP2 receptor, and its importance in targeted therapy, may help identify novel methods to improve management of numerous types of cancer.

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“…For those extra residues between these conserved positions in a particular subfamily, a third digit is added the generic residue number to highlight their positions relative to the nearest conserved position [14]. 5 Â 7D) [44], CCR2 (PDB ID: 5T1A) [45], and CCR9 (PDB ID: 5LWE) [46]. Interestingly, an orthosteric antagonist (BMS-681) and an intracellular antagonist (CCR2-RA-[R]) were found simultaneously in the crystal structure of CCR2 (PDB ID: 5T1A).…”

Section: The Generic Residue Numbers Of Gpcrsmentioning

confidence: 99%

New Binding Sites, New Opportunities for GPCR Drug Discovery

Chan

Dahoun

et al. 2019

Trends in Biochemical Sciences

112

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Many central biological events rely on protein-ligand interactions. The identification and characterization of protein-binding sites for ligands are crucial for the understanding of functions of both endogenous ligands and synthetic drug molecules. G protein-coupled receptors (GPCRs) typically detect extracellular signal molecules on the cell surface and transfer these chemical signals across the membrane, inducing downstream cellular responses via G proteins or b-arrestin. GPCRs mediate many central physiological processes, making them important targets for modern drug discovery. Here, we focus on the most recent breakthroughs in finding new binding sites and binding modes of GPCRs and their potentials for the development of new medicines. The Classical Orthosteric Ligand-Binding Site G protein-coupled receptors (GPCRs; see Glossary) play an essential role in many physiological processes, including vision, olfaction and sense of smell, neuronal signal transmission, cell differentiation, pain, muscle contraction, and hormone secretion, to name a few [1-4]. Thus, GPCRs are among the most important targets for modern medicines (Box 1) [5]. Identifying the ligand-binding sites in target GPCRs is the first important step in a structure-based drug development process [6,7]. Recent progress in illuminating structures of GPCRs show that, besides binding to the traditional orthosteric site, ligands could also bind to remote allosteric sites (Table 1) which provide many new opportunities for drug discovery [7-12]. The traditional orthosteric site (Figure 1A) of GPCRs is close to the extracellular region of receptors, between a highly conserved W 6.48Â48 in transmembrane helix 6 (TM6) and extracellular loop 2 (ECL2). To define the relative position of each amino acid in a TM region, the generic residue numbering methods have been introduced for GPCRs (Box 2) [13]. Most residues (Figure 1B) frequently interacting with orthosteric ligands are in TM3 (positions 3.28

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Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure

Cited by 172 publications

References 39 publications

Could Adenosine Recognize its Receptors with a Stoichiometry Other than 1 : 1?

Could Adenosine Recognize its Receptors with a Stoichiometry Other than 1 : 1?

Prostaglandin EP2 receptor: Novel therapeutic target for human cancers (Review)

New Binding Sites, New Opportunities for GPCR Drug Discovery

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