Metal ion determinants of conantokin dimerization as revealed in the X-ray crystallographic structure of the Cd(2+)/Mg (2+)-con-T[K7gamma] complex.
Predatory sea snails from the Conus family produce a variety of venomous small helical peptides called conantokins that are rich in gamma-carboxyglutamic acid (Gla) residues. As potent and selective antagonists of the N-methyl-D: -aspartate receptor, these peptides are potential therapeutic agents for a variety of neurological conditions. The two most studied members of this family of peptides are con-G and con-T. Con-G has Gla residues at sequence positions 3, 4, 7, 10, and 14, and requires divalent cation binding to adopt a helical conformation. Although both Ca(2+) and Mg(2+) can fulfill this role, Ca(2+) induces dimerization of con-G, whereas the Mg(2+)-complexed peptide remains monomeric. A variant of con-T, con-T[K7gamma] (gamma is Gla), contains Gla residues at the same five positions as in con-G and behaves very similarly with respect to metal ion binding and dimerization; each peptide binds two Ca(2+) ions and two Mg(2+) ions per helix. To understand the difference in metal ion selectivity, affinity, and the dependence on Ca(2+) for dimer formation, we report here the structure of the monomeric Cd(2+)/Mg(2+)-con-T[K7gamma] complex, and, by comparison with the previously published con-T[K7gamma]/Ca(2+) dimer structure, we suggest explanations for both metal ion binding site specificity and metal-ion-dependent dimerization.
Cnudde
Sara E
SE
Department of Chemistry, Michigan State University, East Lansing, 48824, USA.
Prorok
Mary
M
Castellino
Francis J
FJ
Geiger
James H
JH
D002104:Cadmium / Q000737:chemistry*; D002151:Calorimetry; D020916:Conotoxins; D018360:Crystallography, X-Ray; D019281:Dimerization; D036341:Intercellular Signaling Peptides and Proteins; D007477:Ions / Q000737:chemistry; D008274:Magnesium / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D008978:Mollusk Venoms / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification; D009942:Organometallic Compounds / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification
D020916:Conotoxins; D036341:Intercellular Signaling Peptides and Proteins; D007477:Ions; D008978:Mollusk Venoms; D009942:Organometallic Compounds; D010455:Peptides; D002104:Cadmium; C063571:conantokin-T; D008274:Magnesium