loading page

Mapping Co-regulatory Interactions among Ligand Binding sites in RyR1
  • +1
  • Venkat Chirasani,
  • Konstantin Popov,
  • Gerhard Meissner,
  • Nikolay Dokholyan
Venkat Chirasani
University of North Carolina at Chapel Hill School of Medicine

Corresponding Author:[email protected]

Author Profile
Konstantin Popov
University of North Carolina at Chapel Hill School of Medicine
Author Profile
Gerhard Meissner
University of North Carolina at Chapel Hill School of Medicine
Author Profile
Nikolay Dokholyan
Penn State College of Medicine Department of Pharmacology
Author Profile


Ryanodine receptor 1 (RyR1) is an intracellular calcium ion (Ca2+) release channel required for skeletal muscle contraction. Although cryo-electron microscopy identified binding sites of three coactivators Ca2+, ATP and caffeine (CFF), the mechanism of co-regulation and synergy of these activators is unknown. Here, we report allosteric connections among the three ligand binding sites and pore region in (i) Ca2+ bound-closed, (ii) ATP/CFF bound- closed, (iii) Ca2+/ATP/CFF bound-closed, and (iv) Ca2+/ATP/CFF bound-open RyR1 states. We identified two dominant interactions that mediate interactions between the Ca2+ binding site and pore region in Ca2+ bound-closed state, which partially overlapped with the pore communications in ATP/CFF bound-closed RyR1 state. In Ca2+/ATP/CFF bound-closed and -open RyR1 states, co-regulatory interactions were analogous to communications in the Ca2+ bound-closed and ATP/CFF bound- closed states. Both ATP- and CFF- binding sites mediate communication between the Ca2+ binding site and the pore region in Ca2+/ATP/CFF bound - open RyR1 structure. We conclude that Ca2+, ATP, and CFF propagate their effects to the pore region through a network of overlapping interactions that mediate allosteric control and molecular synergy in channel regulation.
09 Apr 2021Submitted to PROTEINS: Structure, Function, and Bioinformatics
12 Apr 2021Submission Checks Completed
12 Apr 2021Assigned to Editor
03 May 2021Reviewer(s) Assigned
04 Jun 2021Review(s) Completed, Editorial Evaluation Pending
04 Aug 2021Editorial Decision: Revise Minor
05 Aug 20211st Revision Received
25 Aug 2021Submission Checks Completed
25 Aug 2021Assigned to Editor
25 Aug 2021Editorial Decision: Accept