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

Scientific Reports
Aneesh ChandranTaufiq Rahman

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 ~100 Å 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 ear...Continue Reading

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Citations

Nov 16, 2019·Annual Review of Physiology·Kozo Hamada, Katsuhiko Mikoshiba
Jun 9, 2020·The Journal of Chemical Physics·Pranav GuptaJack H Freed
Apr 16, 2020·Journal of Clinical Medicine·Jessica GambardellaGaetano Santulli
Dec 29, 2020·Expert Opinion on Drug Discovery·Jessica GambardellaGaetano Santulli
Feb 27, 2021·The Biochemical Journal·Giuliano Molinari, Elsa Nervo

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Methods Mentioned

BETA
PCA

Software Mentioned

Gaussian
OPLS
Amber
Modeler
PyMOL Molecular Graphics System
pyPcazip
MODELLER9v16
Quark
VMD
Molecular Mechanics

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