9E1E

Structure of RyR1 in the primed state in the presence of uracil

This is a non-PDB format compatible entry.

Summary for 9E1E

• Entry DOI: 10.2210/pdb9e1e/pdb
• EMDB information: 47391
• Descriptor: Ryanodine receptor 1, Peptidyl-prolyl cis-trans isomerase FKBP1A, ADENOSINE-5'-TRIPHOSPHATE, ... (6 entities in total)
• Functional Keywords: calcium channel, transport protein, sarcoplasmic reticulum
• Biological source: Oryctolagus cuniculus (rabbit); More
• Total number of polymer chains: 8
• Total formula weight: 2314404.34

Authors

Miotto, M.C.,Marks, A.R. (deposition date: 2024-10-21, release date: 2024-10-30, Last modification date: 2025-06-25)

Primary citation

Miotto, M.C.,Luna-Figueroa, E.,Tchagou, C.,Bahlouli, L.,Reiken, S.,Dridi, H.,Liu, Y.,Weninger, G.,Marks, A.R.
Targeting ryanodine receptors with allopurinol and xanthine derivatives for the treatment of cardiac and musculoskeletal weakness disorders.
Proc.Natl.Acad.Sci.USA, 122:e2422082122-e2422082122, 2025

PubMed Abstract: Ryanodine receptors (RyRs) are intracellular Ca channels essential for muscle contraction. Caffeine, a xanthine derivative, has been known for decades to increase muscle contraction and enhance activation of RyRs by increasing the sensitivity to Ca. We previously showed that xanthine, the only physiologically relevant xanthine derivative, also binds to and activates RyR2. Most xanthine derivatives and analogs are safe and widely prescribed, with the most popular being the xanthine oxidoreductase inhibitor allopurinol (~15M yearly prescriptions in USA). We propose that xanthine derivatives and analogs that enhance RyRs activity could be used for lead optimization and eventually for the treatment of the diseases that exhibit decreased muscle contraction and reduced RyRs activity, such as RyR1-related diseases, sarcopenia, and heart failure. Here, we show by cryo-EM that xanthine derivatives, analogs, and other related compounds bind to the xanthine/caffeine binding site and activate RyR1, and identify 4-oxopyrimidine as the minimal motif necessary for such interaction.

PubMed: 40512792
DOI: 10.1073/pnas.2422082122

Experimental method

ELECTRON MICROSCOPY (2.92 Å)