Chandran, Aneesh and Chee, Xavier and Prole, David L and Rahman, Taufiq (2019) Exploration of inositol 1,4,5-trisphosphate (IP3) regulated dynamics of N-terminal domain of IP3 receptor reveals early phase molecular events during receptor activation. In: SCIENTIFIC REPORTS, 9 . p. 2454.
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Abstract
Inositol 1, 4, 5-trisphosphate (IP3) binding at the N-terminus (NT) of IP3 receptor (IP3R) allosterically triggers the opening of a Ca2+-conducting pore located similar to 100 angstrom away from the IP3-binding core (IBC). However, the precise mechanism of IP3 binding and correlated domain dynamics in the NT that are central to the IP3R activation, remains unknown. Our all-atom molecular dynamics (MD) simulations recapitulate the characteristic twist motion of the suppressor domain (SD) and reveal correlated `clam closure' dynamics of IBC with IP3-binding, complementing existing suggestions on IP3R activation mechanism. Our study further reveals the existence of inter-domain dynamic correlation in the NT and establishes the SD to be critical for the conformational dynamics of IBC. Also, a tripartite interaction involving Glu283-Arg54-Asp444 at the SD - IBC interface seemed critical for IP3R activation. Intriguingly, during the sub-microsecond long simulation, we observed Arg269 undergoing an SD-dependent flipping of hydrogen bonding between the first and fifth phosphate groups of IP3. This seems to play a major role in determining the IP3 binding affinity of IBC in the presence/absence of the SD. Our study thus provides atomistic details of early molecular events occurring within the NT during and following IP3 binding that lead to channel gating.
| Item Type: | Journal Article |
|---|---|
| Publication: | SCIENTIFIC REPORTS |
| Publisher: | NATURE PUBLISHING GROUP |
| Additional Information: | Copyright of this article belongs to NATURE PUBLISHING GROUP |
| Department/Centre: | Division of Biological Sciences > Molecular Biophysics Unit |
| Date Deposited: | 26 Mar 2019 07:48 |
| Last Modified: | 26 Mar 2019 07:48 |
| URI: | http://eprints.iisc.ac.in/id/eprint/61933 |
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