PMID- 32557910
OWN - NLM
STAT- MEDLINE
DCOM- 20210208
LR  - 20210208
IS  - 1097-0134 (Electronic)
IS  - 0887-3585 (Linking)
VI  - 88
IP  - 11
DP  - 2020 Nov
TI  - Investigating dual Ca(2+) modulation of the ryanodine receptor 1 by molecular 
      dynamics simulation.
PG  - 1528-1539
LID - 10.1002/prot.25971 [doi]
AB  - The ryanodine receptors (RyR) are essential to calcium signaling in striated 
      muscles. A deep understanding of the complex Ca(2+) -activation/inhibition 
      mechanism of RyRs requires detailed structural and dynamic information for RyRs 
      in different functional states (eg, with Ca(2+) bound to activating or inhibitory 
      sites). Recently, high-resolution structures of the RyR isoform 1 (RyR1) were 
      solved by cryo-electron microscopy, revealing the location of a Ca(2+) binding 
      site for activation. Toward elucidating the Ca(2+) -modulation mechanism of RyR1, 
      we performed extensive molecular dynamics simulation of the core RyR1 structure 
      in the presence and absence of activating and solvent Ca(2+) (total simulation 
      time is >5 mus). In the presence of solvent Ca(2+) , Ca(2+) binding to the 
      activating site enhanced dynamics of RyR1 with higher inter-subunit flexibility, 
      asymmetric inter-subunit motions, outward domain motions and partial pore 
      dilation, which may prime RyR1 for subsequent channel opening. In contrast, the 
      solvent Ca(2+) alone reduced dynamics of RyR1 and led to inward domain motions 
      and pore contraction, which may cause inhibition. Combining our simulation with 
      the map of disease mutation sites in RyR1, we constructed a wiring diagram of key 
      domains coupled via specific hydrogen bonds involving the mutation sites, some of 
      which were modulated by Ca(2+) binding. The structural and dynamic information 
      gained from this study will inform future mutational and functional studies of 
      RyR1 activation and inhibition by Ca(2+) .
CI  - (c) 2020 Wiley Periodicals LLC.
FAU - Zheng, Wenjun
AU  - Zheng W
AUID- ORCID: 0000-0002-6236-9765
AD  - Department of Physics, University at Buffalo, Buffalo, New York, USA.
FAU - Wen, Han
AU  - Wen H
AUID- ORCID: 0000-0003-4680-4218
AD  - Department of Physics, University at Buffalo, Buffalo, New York, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200713
PL  - United States
TA  - Proteins
JT  - Proteins
JID - 8700181
RN  - 0 (Cations, Divalent)
RN  - 0 (Protein Subunits)
RN  - 0 (Ryanodine Receptor Calcium Release Channel)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Allosteric Regulation
MH  - Binding Sites
MH  - Calcium/*chemistry/metabolism
MH  - Cations, Divalent
MH  - Gene Expression
MH  - Humans
MH  - Hydrogen Bonding
MH  - *Molecular Dynamics Simulation
MH  - *Mutation
MH  - Principal Component Analysis
MH  - Protein Binding
MH  - Protein Conformation, alpha-Helical
MH  - Protein Conformation, beta-Strand
MH  - Protein Interaction Domains and Motifs
MH  - Protein Subunits/*chemistry/genetics/metabolism
MH  - Ryanodine Receptor Calcium Release Channel/*chemistry/genetics/metabolism
MH  - Thermodynamics
OTO - NOTNLM
OT  - activation
OT  - allosteric coupling
OT  - calcium binding
OT  - disease mutation
OT  - inhibition
OT  - molecular dynamics
OT  - ryanodine receptor
EDAT- 2020/06/20 06:00
MHDA- 2021/02/09 06:00
CRDT- 2020/06/20 06:00
PHST- 2019/12/01 00:00 [received]
PHST- 2020/05/26 00:00 [revised]
PHST- 2020/06/14 00:00 [accepted]
PHST- 2020/06/20 06:00 [pubmed]
PHST- 2021/02/09 06:00 [medline]
PHST- 2020/06/20 06:00 [entrez]
AID - 10.1002/prot.25971 [doi]
PST - ppublish
SO  - Proteins. 2020 Nov;88(11):1528-1539. doi: 10.1002/prot.25971. Epub 2020 Jul 13.