期刊
CHEMBIOCHEM
卷 11, 期 3, 页码 358-365出版社
WILEY-BLACKWELL
DOI: 10.1002/cbic.200900657
关键词
dendrimers; kinetics; protein models; thiol ligands; vitamin B-12
资金
- University of Bern
- Swiss National Science Foundation
- Marie Curie
- PRIN [PROT.2007T7MSAJ]
- FAA (Fondo d'Ateneo per la Ricerca)
- University of Milano-Bicocca
The third-generation peptide-dendrimer B1 (AcES)(8)(BEA)(4)(K-Amb-Y)(2)BCD-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 (K-a = 5.0 x 10(6) m(-1)) and rapidly (k(2) = 346 M-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 N-3 (AcQS)(8)(BQA)(4)(B-Amb-Y)(2)BCD-NH2 leads to stronger (K-a = 12.0 x 10(6) M-1) but slower (k(2) = 67 M-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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