A bitopic agonist bound to the dopamine 3 receptor reveals a selectivity site.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 39237617.
- Also identified by DOI 10.1038/s41467-024-51993-4 and PMC identifier 11377762.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. Bitopic ligands are covalently joined orthosteric and allosteric pharmacophores with the potential to boost receptor selectivity and improve current medications by reducing off-target side effects. However, the lack of structural information on their binding mode impedes rational design. Here we determine the cryo-EM structure of the hD<sub>3</sub>R:Gα<sub>O</sub>βγ complex bound to the D<sub>3</sub>R selective bitopic agonist FOB02-04A. Structural, functional and computational analyses provide insights into its binding mode and point to a new TM2-ECL1-TM1 region, which requires the N-terminal ordering of TM1, as a major determinant of subtype selectivity in aminergic GPCRs. This region is underexploited in drug development, expands the established secondary binding pocket in aminergic GPCRs and could potentially be used to design novel and subtype selective drugs.
Medical subject headings
- Cryoelectron Microscopy
- Receptors, Dopamine D3