Differential molecular information of maurotoxin peptide recognizing IK(Ca) and Kv1.2 channels explored by computational simulation.
BACKGROUND
Scorpion toxins are invaluable tools for ion channel research and are potential drugs for human channelopathies. However, it is still an open task to determine the molecular basis underlying the diverse interactions between toxin peptides and ion channels. The inhibitory peptide Maurotoxin (MTX) recognized the distantly related IK(Ca) and Kv1.2 channel with approximately the same potency and using the same functional residues, their differential binding mechanism remain elusive. In this study, we applied computational methods to explore the differential binding modes of MTX to Kv1.2 and IK(Ca) channels, which would help to understand the diversity of channel-toxin interactions and accelerate the toxin-based drug design.


RESULTS
A reasonably stable MTX-IK(Ca) complex was obtained by combining various computational methods and by in-depth comparison with the previous model of the MTX-Kv1.2 complex. Similarly, MTX adopted the β-sheet structure as the interacting surface for binding both channels, with Lys23 occluding the pore. In contrast, the other critical residues Lys27, Lys30, and Tyr32 of MTX adopted distinct interactions when associating with the IK(Ca) channel. In addition, the residues Gln229, Ala230, Ala233, and Thr234 on the IK(Ca) channel turret formed polar and non-polar interactions with MTX, whereas the turret of Kv1.2 was almost not involved in recognizing MTX. In all, the pairs of interacting residues on MTX and the IK(Ca) channel of the bound complex indicated that electrostatic and Van der Waal interactions contributed equally to the formation of a stable MTX-IK(Ca) complex, in contrast to the MTX-Kv1.2 binding that is dominantly mediated by electrostatic forces.


CONCLUSIONS
Despite sharing similar pharmacological profiles toward both IK(Ca) and Kv1.2 channels, MTX adopted totally diverging modes in the two association processes. All the molecular information unveiled here could not only offer a better understanding about the structural differences between the IK(Ca) and Kv1.2 channels, but also provide novel structural clues that will help in the designing of more selective molecular probes to discriminate between these two channels.
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, PR China.
Hong
H
Yi
Su
S
Qiu
Yingliang
Y
Wu
Wenxin
W
Li
Baoshan
B
Wang
D003198:Computer Simulation; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000737:chemistry / Q000378:metabolism*; D051663:Kv1.2 Potassium Channel / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D024681:Potassium Channels, Calcium-Activated; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D012604:Scorpion Venoms / Q000737:chemistry* / Q000378:metabolism*
D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D051663:Kv1.2 Potassium Channel; D024681:Potassium Channels, Calcium-Activated; D024642:Potassium Channels, Voltage-Gated; D012604:Scorpion Venoms; C104498:maurotoxin
Proteins. 2008 Feb 15;70(3):844-54
17729277
J Proteome Res. 2007 Feb;6(2):611-20
17269718
Mol Pharmacol. 2004 Nov;66(5):1103-12
15286210
Toxicon. 2004 Jun 15;43(8):877-86
15208020
J Proteome Res. 2008 Nov;7(11):4890-7
18937510
Curr Med Chem. 2007;14(13):1437-57
17584055
Chem Rev. 2008 May;108(5):1744-73
18476673
Nature. 2006 Apr 13;440(7086):959-62
16612389
Nat Rev Drug Discov. 2003 Oct;2(10):790-802
14526382
Neuron. 1995 Nov;15(5):1169-81
7576659
Biophys J. 2002 Nov;83(5):2595-609
12414693
J Mol Biol. 2002 Apr 26;318(2):417-28
12051848
Pharmacol Rev. 2005 Dec;57(4):473-508
16382104
Trends Pharmacol Sci. 2003 May;24(5):222-7
12767720
Toxicon. 2004 Jun 15;43(8):973-80
15208030
FEBS Lett. 1997 Apr 14;406(3):284-90
9136903
Biophys J. 2000 Aug;79(2):776-87
10920011
Neuron. 1996 Feb;16(2):399-406
8789954
Nucleic Acids Res. 2000 Jan 1;28(1):235-42
10592235
Biophys J. 2004 Jul;87(1):105-12
15240449
Mol Pharmacol. 2003 Feb;63(2):409-18
12527813
Nature. 2003 Mar 13;422(6928):180-5
12629550
Science. 1998 Apr 3;280(5360):106-9
9525854
Biophys J. 2001 Apr;80(4):1659-69
11259281
J Immunol. 2004 Jul 15;173(2):776-86
15240664
Proteins. 2003 Jul 1;52(1):80-7
12784371
Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8151-6
10884437
Pharmacol Rev. 2005 Dec;57(4):463-72
16382103
J Biol Chem. 2008 Jul 4;283(27):19058-65
18480054
Biochimie. 2000 Sep-Oct;82(9-10):861-8
11086216
J Chem Inf Model. 2009 Jul;49(7):1831-8
19499912
Nat Biotechnol. 2005 Apr;23(4):399
15815650
Science. 1995 Apr 14;268(5208):307-10
7716527
Eur J Biochem. 1996 Dec 15;242(3):491-8
9022673
J Biol Chem. 2004 Dec 31;279(53):55690-6
15498765