The third-generation peptide-dendrimer B1 (AcES)8(BEA) 4(K-Amb-Y)2BCD-NH2 (B=branching (S)-2,3-diaminopropanoic acid, K=branching lysine, Amb=4-aminomethyl-benzoic acid) is the first synthetic model for cobalamin-binding proteins and binds cobalamin strongly (Ka=5.0×106M-1) and rapidly (k2= 346m-1 s-1) by coordination of cobalt to the cysteine residue at the dendrimer core. A structure-activity relationship study is reported concerning the role of negative charges in binding. Substituting glutamates (E) for glutamines (Q) in the outer branches of B1 to form N3 (AcQS)8(BQA)4(B-Amb-Y)2BCD- NH2 leads to stronger (Ka=12.0×106M -1) but slower (k2= 67M-1 s-1) cobalamin binding. CD and FTIR spectra show that the dendrimers and their cobalamin complexes exist as random-coil structures without aggregation in solution. The hydrodynamic radii of the dendrimers determined by diffusion NMR either remains constant or slightly decreases upon binding to cobalamin; this indicates the formation of compact, presumably hydrophobically collapsed complexes.
Uhlich, N., Natalello, A., Kadam, R., Doglia, S., Reymond, J., Darbre, T. (2010). Structure and binding of peptide-dendrimer ligands to vitamin B12. CHEMBIOCHEM, 11(3), 358-365 [10.1002/cbic.200900657].
Structure and binding of peptide-dendrimer ligands to vitamin B12
NATALELLO, ANTONINO;DOGLIA, SILVIA MARIA
;
2010
Abstract
The third-generation peptide-dendrimer B1 (AcES)8(BEA) 4(K-Amb-Y)2BCD-NH2 (B=branching (S)-2,3-diaminopropanoic acid, K=branching lysine, Amb=4-aminomethyl-benzoic acid) is the first synthetic model for cobalamin-binding proteins and binds cobalamin strongly (Ka=5.0×106M-1) and rapidly (k2= 346m-1 s-1) by coordination of cobalt to the cysteine residue at the dendrimer core. A structure-activity relationship study is reported concerning the role of negative charges in binding. Substituting glutamates (E) for glutamines (Q) in the outer branches of B1 to form N3 (AcQS)8(BQA)4(B-Amb-Y)2BCD- NH2 leads to stronger (Ka=12.0×106M -1) but slower (k2= 67M-1 s-1) cobalamin binding. CD and FTIR spectra show that the dendrimers and their cobalamin complexes exist as random-coil structures without aggregation in solution. The hydrodynamic radii of the dendrimers determined by diffusion NMR either remains constant or slightly decreases upon binding to cobalamin; this indicates the formation of compact, presumably hydrophobically collapsed complexes.
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