Study On The Allosteric Mechanism Of TRPM8 Channel Gating

TRPM8 channel is a nonselective cation channel.It is widely expressed in human body and also participates in many physiological and pathological processes such as thermoregulation,vasoconstriction and relaxation,cell growth and inflammatory pain.The realization of its function depends on the gating of TRPM8,which is regulated by the physical factor?low temperature 8²8?C?and chemical factors?menthol,icilin,PIP₂ etc.?.The well-organized gating conformation transition of TRPM8 channel is the basis of its physiological function,and the understanding of its mechanism is not only an important scientific problem but also the basis of discovering its target drugs.Therefore,it is very important to study the allosteric mechanism of TRPM8 Channel gating.The author constructed the structures of TRPM8 in closed and open state with Homology Modeling,performed Molecular dynamics?MD?simulations and targeted MD simulations and achieved the transition from closed to open state.Based on the analysis of the allosteric processes,the author identified the gating-related functional structure domain,determined the allosteric structure foundation,illuminated the molecular mechanism of the channel activation.We hope that it will shed light on drug designing targeting on TRP channels.Followings are the main results:1.The closed and open structures are successfully constructed based on the crystal structure of TRPV1 by performing homology modeling.As shown in the structures,there are two gates along the pore of TRPM8,the upper gate and the lower gate.2.We performed Targeted molecular dynamics simulations on TRPM8 channel and achieved the transition from the closed to the open state for the first time.Our data indicate that the opening of the upper gate is independent on the lower gate.3.It's shown that the opening of the lower gate is triggered by the twisting of the S4-S5-linker which induces the upward motion of TRP-box and the bending of S6 helix.A weak interaction network is identified that modulates the gating process of the lower gate.