Structure-activity analysis of a Conus peptide blocker of N-type neuronal calcium channels.
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.
Nadasdi
L
L
Neurex Corporation, Menlo Park, California 94025, USA.
Yamashiro
D
D
Chung
D
D
Tarczy-Hornoch
K
K
Adriaenssens
P
P
Ramachandran
J
J
D000595:Amino Acid Sequence; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000737:chemistry* / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D008969:Molecular Sequence Data; D009474:Neurons / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013570:Synaptic Membranes / Q000378:metabolism; D020960:omega-Conotoxins
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D010455:Peptides; D020960:omega-Conotoxins; C078452:ziconotide; D002118:Calcium