Enhanced ligand affinity for receptors in which components of the binding site are independently mobile

Clare R. Trevitt, C. Jeremy Craven, Lilia Milanesi, Karl Syson, Maija-Liisa Mattinen, Julie Perkins, Arto Annila, Christopher A. Hunter, Jonathan P. Waltho

Research output: Contribution to journalArticleScientificpeer-review

7 Citations (Scopus)

Abstract

Using calmodulin antagonism as a model, it is demonstrated that, under circumstances in which binding sites are motionally independent, it is possible to create bifunctional ligands that bind with significant affinity enhancement over their monofunctional counterparts. Suitable head groups were identified by using a semiquantitative screen of monofunctional tryptophan analogs. Two bifunctional ligands, which contained two copies of the highest-affinity head group tethered by rigid linkers, were synthesized. The bifunctional ligands bound to calmodulin with a stoichiometry of 1:1 and with an affinity enhancement over their monofunctional counterparts; the latter bound with a stoichiometry of 2:1 ligand:protein. A lower limit to the effective concentrations of the domains of calmodulin relative to each other (0.2–2 mM) was determined. A comparable effective concentration was achieved for bifunctional ligands based on higher-affinity naphthalene sulphonamide derivatives.
Original languageEnglish
Pages (from-to)89-97
JournalChemistry and Biology
Volume12
Issue number1
DOIs
Publication statusPublished - 2005
MoE publication typeA1 Journal article-refereed

Keywords

  • ligands
  • peptide-mimic ligands
  • naphthalene ligands
  • bifunctional ligands
  • calmodulin

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    Trevitt, C. R., Craven, C. J., Milanesi, L., Syson, K., Mattinen, M-L., Perkins, J., Annila, A., Hunter, C. A., & Waltho, J. P. (2005). Enhanced ligand affinity for receptors in which components of the binding site are independently mobile. Chemistry and Biology, 12(1), 89-97. https://doi.org/10.1016/j.chembiol.2004.11.007