Nadasdi L, Yamashiro D, Chung D, Tarczy-Hornoch K, Adriaenssens P, Ramachandran J
Neurex Corporation, Menlo Park, California 94025, USA.
Biochemistry. 1995 Jun 27;34(25):8076-81. doi: 10.1021/bi00025a013.
The synthetic peptide SNX-111 corresponding to the sequence of the omega-conopeptide MVIIA from the venom of the marine snail Conus magus is a highly potent and selective antagonist of N-type calcium channels. We have synthesized and characterized a large number of analogs of SNX-111 in order to elucidate the structural features of the peptide involved in blocking N-type calcium channels. Comparison of the binding of SNX-111 and its analogs to rat brain synaptosomal membranes rich in N-type channels revealed that, among the four lysines and two arginines in the molecule, lysine in position 2 and arginines at position 10 and 21 are important for the interaction of SNX-111 with N-type channels. The importance of the middle segment from residues 9 through 14 for this binding interaction was revealed by substitution of the individual residues as well as by the construction of hybrid peptides in which the residues 9-12 in SNX-111 and another conopeptide, SNX-183, corresponding to a peptide SVIB from Conus striatus, were interchanged. Introduction of the sequence SRLM from SNX-111 in place of RKTS in position 9-12 in SNX-183 resulted in a 38-fold increase in affinity.
合成肽SNX - 111对应于海蜗牛芋螺毒液中的ω - 芋螺毒素MVIIA的序列，是一种高效且选择性的N型钙通道拮抗剂。我们合成并表征了大量SNX - 111的类似物，以阐明该肽阻断N型钙通道所涉及的结构特征。将SNX - 111及其类似物与富含N型通道的大鼠脑突触体膜进行结合比较，结果显示，在该分子的四个赖氨酸和两个精氨酸中，第2位的赖氨酸以及第10位和第21位的精氨酸对于SNX - 111与N型通道的相互作用很重要。通过单个残基的替换以及构建杂合肽揭示了第9至14位残基的中间片段对于这种结合相互作用的重要性，在杂合肽中，SNX - 111的第9 - 12位残基与另一种芋螺毒素SNX - 183（对应于条纹芋螺的肽SVIB）进行了互换。用SNX - 111的序列SRLM替换SNX - 183中第9 - 12位的RKTS，导致亲和力增加了38倍。
