Download MendeleyInsight into binding of endogenous neurosteroid ligands to the sigma-1 receptor.
Fu, C., Xiao, Y., Zhou, X., Sun, Z.(2024) Nat Commun 15: 5619-5619
- PubMed: 38965213
- DOI: https://doi.org/10.1038/s41467-024-49894-7
- Primary Citation of Related Structures:
8W4B, 8W4C, 8W4D, 8W4E, 8WUE, 8WWB, 8YBB - PubMed Abstract:
The sigma-1 receptor (考1R) is a non-opioid membrane receptor, which responds to a diverse array of synthetic ligands to exert various pharmacological effects. Meanwhile, candidates for endogenous ligands of 考1R have also been identified. However, how endogenous ligands bind to 考1R remains unknown. Here, we present crystal structures of 考1R from Xenopus laevis (xl考1R) bound to two endogenous neurosteroid ligands, progesterone (a putative antagonist) and dehydroepiandrosterone sulfate (DHEAS) (a putative agonist), at 2.15-3.09? ? resolutions. Both neurosteroids bind to a similar location in xl考1R mainly through hydrophobic interactions, but surprisingly, with opposite binding orientations. DHEAS also forms hydrogen bonds with xl考1R, whereas progesterone interacts indirectly with the receptor through water molecules near the binding site. Binding analyses are consistent with the xl考1R-neurosteroid complex structures. Furthermore, molecular dynamics simulations and structural data reveal a potential water entry pathway. Our results provide insight into binding of two endogenous neurosteroid ligands to 考1R.
Organizational Affiliation:
Department of Integrated Traditional Chinese and Western Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
