8W4C

The sigma-1 receptor from Xenopus laevis in complex with progesterone by soaking

Summary for 8W4C

• Entry DOI: 10.2210/pdb8w4c/pdb
• Descriptor: Sigma non-opioid intracellular receptor 1, PROGESTERONE (3 entities in total)
• Functional Keywords: sigma receptor, s1r, endogenous ligand, neurosteroid, p4, membrane protein
• Biological source: Xenopus laevis (African clawed frog)
• Total number of polymer chains: 1
• Total formula weight: 26034.78

Authors

Xiao, Y.,Fu, C.,Sun, Z.,Zhou, X. (deposition date: 2023-08-23, release date: 2024-07-17)

Primary citation

Fu, C.,Xiao, Y.,Zhou, X.,Sun, Z.
Insight into binding of endogenous neurosteroid ligands to the sigma-1 receptor.
Nat Commun, 15:5619-5619, 2024

PubMed Abstract: The sigma-1 receptor (σ1R) 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 σ1R have also been identified. However, how endogenous ligands bind to σ1R remains unknown. Here, we present crystal structures of σ1R from Xenopus laevis (xlσ1R) bound to two endogenous neurosteroid ligands, progesterone (a putative antagonist) and dehydroepiandrosterone sulfate (DHEAS) (a putative agonist), at 2.15-3.09  Å resolutions. Both neurosteroids bind to a similar location in xlσ1R mainly through hydrophobic interactions, but surprisingly, with opposite binding orientations. DHEAS also forms hydrogen bonds with xlσ1R, whereas progesterone interacts indirectly with the receptor through water molecules near the binding site. Binding analyses are consistent with the xlσ1R-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 σ1R.

PubMed: 38965213
DOI: 10.1038/s41467-024-49894-7

Experimental method

X-RAY DIFFRACTION (2.676 Å)