Claudia Llinás del Torrent

Universitat Autònoma de Barcelona

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Leonardo Pardo

Universitat Autònoma de Barcelona

Gemma Navarro

Instituto de Salud Carlos III

Rafael Franco

Universitat de Barcelona

Nil Casajuana‐Martin

Universitat Autònoma de Barcelona

Jaume Lillo

Universitat de Barcelona

Iu Raïch

Universitat de Barcelona

Nagarajan Vaidehi

Beckman Research Institute

Sergi Ferré

National Institute on Drug Abuse

Wijnand J. C. van der Velden

Beckman Research Institute

Jeevan Tewari

Duke Medical Center

Cooperative Institutions

Universitat de Barcelona

National Institute on Drug Abuse

Biomedical Research Networking Center on Neurodegenerative Diseases

National Institutes of Health

Universitat Autònoma de Barcelona

Bellvitge University Hospital

Institut d'Investigació Biomédica de Bellvitge

Instituto de Salud Carlos III

Centro de Investigación Biomédica en Red

University of California, San Francisco

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Engineered odorant receptors illuminate the basis of odour discrimination

Nature (2024)

Claire A. de March Ning Ma Christian B. Billesbølle Jeevan Tewari Claudia Llinás del Torrent

Homology

Structural motif

Molecular Recognition

10.1038/s41586-024-08126-0

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Citations (5)

The ADORA1 mutation linked to early-onset Parkinson’s disease alters adenosine A1-A2A receptor heteromer formation and function

Biomedicine & Pharmacotherapy (2022)

Laura I. Sarasola Claudia Llinás del Torrent Andrea Pérez Arévalo Josep Argerich Nil Casajuana‐Martin

Adenosine modulates neurotransmission through inhibitory adenosine A1 receptors (A1Rs) and stimulatory A2A receptors (A2ARs). These G protein-coupled receptors are involved in motor function and related to neurodegenerative diseases such as Parkinson's disease (PD). An autosomal-recessive mutation (G2797.44S) within the transmembrane helix (TM) 7 of A1R (A1RG279S) has been associated with the development of early onset PD (EOPD). Here, we aimed at investigating the impact of this mutation on the structure and function of the A1R and the A1R-A2AR heteromer. Our results revealed that the G2797.44S mutation does not alter A1R expression, ligand binding, constitutive activity or coupling to transducer proteins (Gαi, Gαq, Gα12/13, Gαs, β-arrestin2 and GRK2) in transfected HEK-293 T cells. However, A1RG279S weakened the ability of A1R to heteromerize with A2AR, as shown in a NanoBiT assay, which led to the disappearance of the heteromerization-dependent negative allosteric modulation that A1R imposes on the constitutive activity and agonist-induced activation of the A2AR. Molecular dynamic simulations allowed to propose an indirect mechanism by which the G2797.44S mutation in TM 7 of A1R weakens the TM 5/6 interface of the A1R-A2AR heteromer. Therefore, it is demonstrated that a PD linked ADORA1 mutation is associated with dysfunction of adenosine receptor heteromerization. We postulate that a hyperglutamatergic state secondary to increased constitutive activity and sensitivity to adenosine of A2AR not forming heteromers with A1R could represent a main pathogenetic mechanism of the EOPD associated with the G2797.44S ADORA1 mutation.

Adenosine A2A receptor

10.1016/j.biopha.2022.113896

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Insights of schizophrenia associated dopamine D2 receptor variants: interplay with the adenosinergic system

Neuroscience Applied (2023)

Francisco Ciruela Marta Valle-León Claudia Llinás del Torrent Paula Álvarez-Montoya Marc López‐Cano

Adenosinergic

10.1016/j.nsa.2023.103686

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Pharmacological targeting of G protein-coupled receptor heteromers

Pharmacological Research (2022)

Estefanía Moreno Nil Casajuana‐Martin Michael Coyle Baruc Campos Ewa Galaj

A main rationale for the role of G protein-coupled receptor (GPCR) heteromers as targets for drug development is the putative ability of selective ligands for specific GPCRs to change their pharmacological properties upon GPCR heteromerization. The present study provides a proof of concept for this rationale by demonstrating that heteromerization of dopamine D1 and D3 receptors (D1R and D3R) influences the pharmacological properties of three structurally similar selective dopamine D3R ligands, the phenylpiperazine derivatives PG01042, PG01037 and VK4–116. By using D1R-D3R heteromer-disrupting peptides, it could be demonstrated that the three D3R ligands display different D1R-D3R heteromer-dependent pharmacological properties: PG01042, acting as G protein-biased agonist, counteracted D1R-mediated signaling in the D1R-D3R heteromer; PG01037, acting as a D3R antagonist cross-antagonized D1R-mediated signaling in the D1R-D3R heteromer; and VK4–116 specifically acted as a ß-arrestin-biased agonist in the D1R-D3R heteromer. Molecular dynamics simulations predicted potential molecular mechanisms mediating these qualitatively different pharmacological properties of the selective D3R ligands that are dependent on D1R-D3R heteromerization. The results of in vitro experiments were paralleled by qualitatively different pharmacological properties of the D3R ligands in vivo. The results supported the involvement of D1R-D3R heteromers in the locomotor activation by D1R agonists in reserpinized mice and L-DOPA-induced dyskinesia in rats, highlighting the D1R-D3R heteromer as a main pharmacological target for L-DOPA-induced dyskinesia in Parkinson’s disease. More generally, the present study implies that when suspecting its pathogenetic role, a GPCR heteromer, and not its individual GPCR units, should be considered as main target for drug development.

Functional selectivity

10.1016/j.phrs.2022.106476

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Computational Drug Design Applied to the Study of Metabotropic Glutamate Receptors

Molecules (2019)

Claudia Llinás del Torrent Laura Pérez‐Benito Gary Tresadern

Metabotropic glutamate (mGlu) receptors are a family of eight GPCRs that are attractive drug discovery targets to modulate glutamate action and response. Here we review the application of computational methods to the study of this family of receptors. X-ray structures of the extracellular and 7-transmembrane domains have played an important role to enable structure-based modeling approaches, whilst we also discuss the successful application of ligand-based methods. We summarize the literature and highlight the areas where modeling and experiment have delivered important understanding for mGlu receptor drug discovery. Finally, we offer suggestions of future areas of opportunity for computational work.

Class C GPCR

10.3390/molecules24061098

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The computational modeling of allosteric modulation of metabotropic glutamate receptors

Advances in pharmacology (2020)

Laura Pérez‐Benito Claudia Llinás del Torrent Leonardo Pardo Gary Tresadern

10.1016/bs.apha.2020.02.004

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Citations (1)

Structural basis of odorant recognition by a human odorant receptor

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Christian B. Billesbølle Claire A. de March Wijnand J. C. van der Velden Ning Ma Jeevan Tewari

Abstract Our sense of smell enables us to navigate a vast space of chemically diverse odor molecules. This task is accomplished by the combinatorial activation of approximately 400 olfactory G protein-coupled receptors (GPCRs) encoded in the human genome 1–3 . How odorants are recognized by olfactory receptors (ORs) remains mysterious. Here we provide mechanistic insight into how an odorant binds a human olfactory receptor. Using cryogenic electron microscopy (cryo-EM), we determined the structure of active human OR51E2 bound to the fatty acid propionate. Propionate is bound within an occluded pocket in OR51E2 and makes specific contacts critical to receptor activation. Mutation of the odorant binding pocket in OR51E2 alters the recognition spectrum for fatty acids of varying chain length, suggesting that odorant selectivity is controlled by tight packing interactions between an odorant and an olfactory receptor. Molecular dynamics simulations demonstrate propionate-induced conformational changes in extracellular loop 3 to activate OR51E2. Together, our studies provide a high-resolution view of chemical recognition of an odorant by a vertebrate OR, providing insight into how this large family of GPCRs enables our olfactory sense.

10.1101/2022.12.20.520951

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Citations (4)

Structural basis of odorant recognition by a human odorant receptor

Nature (2023)

Christian B. Billesbølle Claire A. de March Wijnand J. C. van der Velden Ning Ma Jeevan Tewari

Molecular Recognition

10.1038/s41586-023-05798-y

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Citations (89)

Contributors

Elsevier eBooks (2023)

Vahid Reza Askari Ester Aso Vafa Baradaran Rahimi Andrés M. Baraibar Robert W. Barnes

10.1016/b978-0-323-90877-1.09988-5

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Citations (0)

Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling

Pharmacological Research (2024)

Gemma Navarro Marc Gómez‐Autet Paula Morales Joan Biel Rebassa Claudia Llinás del Torrent

G protein-coupled receptors (GPCRs) exist within a landscape of interconvertible conformational states and in dynamic equilibrium between monomers and higher-order oligomers, both influenced by ligand binding. Here, we show that a homobivalent ligand formed by equal chromenopyrazole moieties as pharmacophores, connected by 14 methylene units, can modulate the dynamics of the cannabinoid CB

Bivalent (engine)

10.1016/j.phrs.2024.107363

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Citations (4)