| Autor: |
Yao J; School of Life Sciences, Liaoning Normal University, Dalian116081, China.; Department of Occupational and Environmental Health, Faculty of Naval Medicine, Naval Medical University (Second Military Medical University), Shanghai 200433, China., Hua X; Department of Occupational and Environmental Health, Faculty of Naval Medicine, Naval Medical University (Second Military Medical University), Shanghai 200433, China., Huo W; The 305 Hospital of PLA, Beijing 100017, China., Xiao L; Department of Medicine and Cardiovascular Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin 53188, United States.; Department of Forensic Toxicological Analysis, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610017, China., Wang Y; Department of Occupational and Environmental Health, Faculty of Naval Medicine, Naval Medical University (Second Military Medical University), Shanghai 200433, China., Tang Q; Central Medical District of Chinese, PLA General Hospital, Beijing 100120, China., Valdivia CR; Department of Medicine and Cardiovascular Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin 53188, United States., Valdivia HH; Department of Medicine and Cardiovascular Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin 53188, United States., Dong W; School of Life Sciences, Liaoning Normal University, Dalian116081, China., Xiao L; Department of Occupational and Environmental Health, Faculty of Naval Medicine, Naval Medical University (Second Military Medical University), Shanghai 200433, China. |
| Abstrakt: |
Calcin is a group ligand with high affinity and specificity for the ryanodine receptors (RyRs). Little is known about the effect of its acidic residues on the spacial structure as well as the interaction with RyRs. We screened the opicalcin1 acidic mutants and investigated the effect of mutation on activity. The results indicated that all acidic mutants maintained the structural features, but their surface charge distribution underwent significant changes. Molecular docking and dynamics simulations were used to analyze the interaction between opicalcin1 mutants and RyRs, which demonstrated that all opicalcin1 mutants effectively bound to the channel domain of RyR1. This stable binding induced a pronounced asymmetry in the structure of the RyR tetramer, exhibiting a high degree of structural dissimilarity. [ 3 H]Ryanodine binding to RyR1 was enhanced in D2A and D15A, which was similar to opicalcin1, but that effect was suppressed in E12A and E29A and reversed for the DE-4A, thereby inhibiting ryanodine binding. Opicalcin1 and DE-4A also exhibited the ability to form stable docking structures with RyR2. Acidic residues play a crucial role in the structure of calcin and its functional interaction with RyRs that is beneficial for the calcin optimization to develop more active peptide lead compounds for RyR-related diseases. |
