瞬时受体电位M8型离子通道选择性滤器的三维结构计算建模
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摘要
目的:构建瞬时受体电位M8型(TRPM8)离子通道选择性滤器结构域的三维结构模型。方法:在Rosetta计算结构生物学工具包中,使用基于运动回路闭合算法的从头计算,对TRPM8离子通道选择性滤器结构域进行多轮计算建模。结果:经过9轮计算得到了能量最低且结构收敛的TRPM8通道选择性滤器结构域的三维结构模型,发现D918位点的侧链并不指向离子流过的孔区中心,而Q914、D920和T923位点的侧链指向孔区中心;糖基化位点N934位于孔区外侧,其侧链指向胞外水环境。结论:构建了TRPM8通道选择性滤器结构域的三维结构模型,为理解该通道的离子选择性及相关机制提供了较为可靠的结构信息。
Objective: To construct a three-dimensional structural model for the selectivity filter in the transient receptor pontential melastatin 8(TRPM8) ion channel.Methods: In the Rosetta computational structural biology suite, multiple rounds of de novo modeling with the kinematic loop closure algorithm were performed. Results: After nine rounds of computational modeling, we obtained the models of the selectivity filter within the TRPM8 channel with the lowest energy and high convergence. The model showed that the sidechain of D918 points were away from the central ion permeation pathway, while the sidechains of Q914,D920 and T923 pointed towards it. The glycosylation site N934 was located outside the pore region and its side chain directed to the extracellular water environment. Conclusion: A three-dimensional structural model for the selectivity filter in the TRPM8 ion channel was constructed, which provides reliable structural information for exploring the mechanism of ion selectivity.
Objective: To construct a three-dimensional structural model for the selectivity filter in the transient receptor pontential melastatin 8(TRPM8) ion channel.Methods: In the Rosetta computational structural biology suite, multiple rounds of de novo modeling with the kinematic loop closure algorithm were performed. Results: After nine rounds of computational modeling, we obtained the models of the selectivity filter within the TRPM8 channel with the lowest energy and high convergence. The model showed that the sidechain of D918 points were away from the central ion permeation pathway, while the sidechains of Q914,D920 and T923 pointed towards it. The glycosylation site N934 was located outside the pore region and its side chain directed to the extracellular water environment. Conclusion: A three-dimensional structural model for the selectivity filter in the TRPM8 ion channel was constructed, which provides reliable structural information for exploring the mechanism of ion selectivity.
引文
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[24]DRAGONI I,GUIDA E,MCINTYRE P.The cold and menthol receptor TRPM8 contains a functionally important double cysteine motif[J].J Biol Chem,2006,281(49):37353-37360.
[2]MONTELL C,BIRNBAUMER L,FLOCKERZI V,et al.A unified nomenclature for the superfamily of TRPcation channels[J].Mol Cell,2002,9(2):229-231.
[3]DHAKA A,VISWANATH V,PATAPOUTIAN A.Trp ion channels and temperature sensation[J].Annu Rev Neurosci,2006,29:135-161.
[4]PEIER A M,MOQRICH A,HERGARDEN A C,et al.A TRP channel that senses cold stimuli and menthol[J].Cell,2002,108(5):705-715.
[5]MCKEMY D D,NEUHAUSSER W M,JULIUS D.Identification of a cold receptor reveals a general role for TRP channels in thermosensation[J].Nature,2002,416(6876):52-58.
[6]DHAKA A,MURRAY A N,MATHUR J,et al.TRPM8 is required for cold sensation in mice[J].Neuron,2007,54(3):371-378.
[7]YIN Y,WU M,ZUBCEVIC L,et al.Structure of the cold-and menthol-sensing ion channel TRPM8[J].Science,2018,359(6372):237-241.
[8]CAO E,LIAO M,CHENG Y,et al.TRPV1 structures in distinct conformations reveal activation mechanisms[J].Nature,2013,504(7478):113-118.
[9]PAULSEN C E,ARMACHE J P,GAO Y,et al.Structure of the TRPA1 ion channel suggests regulatory mechanisms[J].Nature,2015,525(7570):552.
[10]GAO Y,CAO E,JULIUS D,et al.TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action[J].Nature,2016,534(7607):347-351.
[11]AUTZEN H E,MYASNIKOV A G,CAMPBELL M G,et al.Structure of the human TRPM4 ion channel in a lipid nanodisc[J].Science,2018,359(6372):228-232.
[12]WINKLER P A,HUANG Y,SUN W,et al.Electron cryo-microscopy structure of a human TRPM4 channel[J].Nature,2017,552(7684):200-204.
[13]GUO J,SHE J,ZENG W,et al.Structures of the calcium-activated,non-selective cation channel TRPM4[J].Nature,2017,552(7684):205-209.
[14]ZHANG Z,TóTH B,SZOLLOSI A,et al.Structure of a TRPM2 channel in complex with Ca2+explains unique gating regulation[J/OL].Elife,2018,7:e36409.
[15]LEAVER-FAY A,TYKA M,LEWIS S M,et al.ROSETTA3:an object-oriented software suite for the simulation and design of macromolecules[J].Methods Enzymol,2011,487:545-574.
[16]MANDELL D J,COUTSIAS E A,KORTEMME T.Sub-angstrom accuracy in protein loop reconstruction by robotics-inspired conformational sampling[J].Nat Methods,2009,6(8):551-552.
[17]PETTERSEN E F,GODDARD T D,HUANG C C,et al.UCSF Chimera-a visualization system for exploratory research and analysis[J].J Comput Chem,2004,25(13):1605-1612.
[18]YANG F,XIAO X,CHENG W,et al.Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel[J].Nat Chem Biol,2015,11(7):518-524.
[19]YAROV-YAROVOY V,DECAEN P G,WESTEN-BROEK R E,et al.Structural basis for gating charge movement in the voltage sensor of a sodium channel[J/OL].Proc Natl Acad Sci U S A,2012,109(2):E93-102.
[20]YANG F,XIAO X,LEE B H,et al.The conformational wave in capsaicin activation of transient receptor potential vanilloid 1 ion channel[J].Nat Commun,2018,9(1):2879.
[21]RADDATZ N,CASTILLO J P,GONZALEZ C,et al.Temperature and voltage coupling to channel opening in transient receptor potential melastatin 8(TRPM8)[J].J Biol Chem,2014,289(51):35438-35454.
[22]BIDAUX G,SGOBBA M,LEMONNIER L,et al.Functional and modeling studies of the transmembrane region of the TRPM8 channel[J].Biophys J,2015,109(9):1840-1851.
[23]VELDHUIS N A,LEW M J,ABOGADIE F C,et al.N-glycosylation determines ionic permeability and desensitization of the TRPV1 capsaicin receptor[J].JBiol Chem,2012,287(26):21765-21772.
[24]DRAGONI I,GUIDA E,MCINTYRE P.The cold and menthol receptor TRPM8 contains a functionally important double cysteine motif[J].J Biol Chem,2006,281(49):37353-37360.