Structural basis for α-K toxin specificity for K+ channels revealed through the solution 1H NMR structures of two noxiustoxin-iberiotoxin chimeras

被引:19
作者
Ferrat, G
Bernard, C
Fremont, V
Mullmann, TJ
Giangiacomo, KM
Darbon, H
机构
[1] AFMB, CNRS UMR 6098, F-13402 Marseille 20, France
[2] Temple Univ, Sch Med, Dept Biochem, Philadelphia, PA 19140 USA
关键词
D O I
10.1021/bi010228e
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
Noxiustoxin (NxTX) and iberiotoxin (IbTX) exhibit extraordinary differences in their ability to inhibit current through the large-conductance calcium-activated potassium (maxi-K) and voltage-gated potassium (Kv1.3) channels. The three-dimensional structures of NxTX and IbTX display differences in their alpha/beta turn and in the length of the (alpha -carbon backbone. To understand the role of these differences in defining specificity, we constructed two NxTX mutants, NxTX-IbTX I and NxTX-IbTX II, and solved their solution structures by H-1 NMR spectroscopy. For NxTX-IbTX I, seven amino acids comprising the alpha/beta turn in NxTX are replaced with six amino acids from the corresponding (alpha/beta turn in IbTX (NxTX-YGSSAGA(21-27)FGVDRF(21-26)) In addition, NxTX-IbTX II contained the S14W mutation and deletion of the N- and C-terminal residues. Both NxTX-IbTX I and NxTX-IbTX II exhibit an alpha/beta scaffold structure typical of the alpha -K channel toxins. A helix is present from residues 10 to 19 in NxTX-IbTX I and from residues 13 to 19 in NxTX-IbTX II. The beta -sheet, defined by three antiparallel strands, is one residue longer in NxTX-IbTX I relative to NxTX-IbTX II. The two toxins also differ in the structure of the alpha/beta turn with NxTX-IbTX I resembling that of IbTX and with NxTX-IbTX 11 resembling that of NxTX. These differences in the beta -sheet and alpha/beta turn alter the dimensions of the toxin-channel interaction surface and provide insight into how these NxTX mutations alter K+ channel specificity for the maxi-K and Kvl.3 channels.
引用
收藏
页码:10998 / 11006
页数:9
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