Identification of a Lipid-Exposed Extrahelical Binding Site for Positive Allosteric Modulators of the Dopamine D<sub>2</sub> Receptor
Recently, the first small-molecule positive allosteric modulators (PAMs) of the dopamine D<sub>2</sub> receptor (D<sub>2</sub>R) were identified. The more potent PAM potentiated the effects of D<sub>2</sub>R signaling in vitro and in an in vivo model predictive of anti-Parkinson's efficacy. We reveal, based on the results of our site-directed mutagenesis and molecular dynamics experiments, that this scaffold binds to a hitherto unexploited lipid-exposed extrahelical allosteric site in the D<sub>2</sub>R that lies in a cleft toward the intracellular aspect of the D<sub>2</sub>R defined by residues in transmembrane domains 1 and 7 and helix 8. By binding to this site, the PAM acts to potentiate the binding affinity of efficacious agonists, such as dopamine. Our simulations suggest that the PAM achieves this effect by stabilizing an active-like conformation of the receptor, similar to the G protein-bound state with TM5 and the tyrosine toggle switch playing the major role.
Authors
- J. Robert Lane (ORCID: https://orcid.org/0000-0002-7361-7875)
- Zara A. Sands (ORCID: https://orcid.org/0000-0001-5830-6246)
- Damian Bartuzi (ORCID: https://orcid.org/0000-0001-9927-376X)
- Alastair C. Keen (ORCID: https://orcid.org/0000-0002-0036-757X)
- Caroline Rauffenbart
- Meritxell Canals (ORCID: https://orcid.org/0000-0002-7942-5006)
- Herman D. Lim (ORCID: https://orcid.org/0000-0002-7368-0081)
- Silvia Lovera (ORCID: https://orcid.org/0000-0003-1351-8426)
- Steven J. Charlton (ORCID: https://orcid.org/0000-0001-8841-2752)
- Jens Carlsson (ORCID: https://orcid.org/0000-0003-4623-2977)
- Jonathan A. Javitch (ORCID: https://orcid.org/0000-0001-7395-2967)
- Ali Ates
- Martyn Wood
- Jacqueline R. Glenn
Institutions
- Medical University of Lublin (PL)
- Uppsala University (SE)
- University of Nottingham (GB)
- Science for Life Laboratory (SE)
- Laboratoire de Biologie Physico-Chimique des Protéines Membranaires (FR)
- Queen's Medical Centre (GB)
- Receptors (United States) (US)
- Royal College of Physicians (GB)
- New York State Psychiatric Institute
- Monash University (AU)
- Columbia University (US)
- University of Birmingham (GB)
- UCB Pharma (Belgium) (BE)
Publication Details
- Journal
- ACS Chemical Neuroscience
- Published
- 2025-05-15
- DOI
- https://doi.org/10.1021/acschemneuro.5c00105
- Citations
- 3
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- Columbia University
- Sven och Lilly Lawskis Fond för Naturvetenskaplig Forskning
- Knut och Alice Wallenbergs Stiftelse
- Stiftelsen Olle Engkvist Byggmästare
- Vetenskapsrådet
- Narodowa Agencja Wymiany Akademickiej
- Biotechnology and Biological Sciences Research Council
- National Health and Medical Research Council
- National Institute of Mental Health