Modeling of the outer vestibule and selectivity filter of the L-type Ca2+ channel

被引:56
作者
Lipkind, GM
Fozzard, HA
机构
[1] Univ Chicago, Dept Biochem & Mol Biol, Cardiac Electrophysiol Labs, Chicago, IL 60637 USA
[2] Univ Chicago, Dept Med, Cardiac Electrophysiol Labs, Chicago, IL 60637 USA
关键词
D O I
10.1021/bi010269a
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Using the KcsA bacterial K+ channel crystal structure [Doyle, D.A., et al. (1998) Science 280, 69-74] and the model of the outer vestibule of the Na+ channel [Lipkind, G. M., and Fozzard, I-I. A. (2000) Biochemistry 39, 8161-8170] as structural templates, we propose a structural model of the outer vestibule and selectivity filter of the pore of the Ca2+ channel (alpha (1c) or Ca(V)1.2). The Ca2+ channel P loops were modeled by alpha -helix-turn-beta -strand motifs, with the glutamate residues of the EEEE motif located in the turns. P loops were docked in the extracellular part of the inverted teepee structure formed by S5 and S6 alpha -helices with backbone coordinates from the M1 and M2 helices of the KcsA crystal structure. This construction results in a conical outer vestibule that tapers to the selectivity filter at the bottom. The modeled selectivity ring forms a wide open pore (similar to6 Angstrom) in the absence of Ca2+. When Ca2+ is present (similar to1 muM), all four glutamate side chains move to the center and form a cage around the dehydrated Ca2+ ion, blocking the pore. In the millimolar concentration range, Ca2+ also interacts with two low-affinity sites located externally and internally, which were modeled by the same carboxylate groups of the selectivity filter. Calculation of the resulting electrostatic potentials show that the single Ca2+ ion is located in an electrostatic trap. Only when three Ca2+ ions are bound simultaneously in the high- and low-affinity sites of the selectivity filter is Ca2+ able to overcome electrostatic attraction, permitting Ca2+ flux.
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页码:6786 / 6794
页数:9
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