COOPERATIVITY AND ANTI-COOPERATIVITY BETWEEN LIGAND-BINDING AND THE DIMERIZATION OF RISTOCETIN-A - ASYMMETRY OF A HOMODIMER COMPLEX AND IMPLICATIONS FOR SIGNAL-TRANSDUCTION

Background: Recent work has indicated that dimerization is important i n the mode of action of the vancomycin group of glycopeptide antibioti cs. NMR studies have shown that one member of this group, ristocetin A , forms an asymmetric dimer with two physically different binding site s for cell wall peptides. Ligand binding by ristocetin A and dimerizat ion are slightly anti-cooperative. In contrast, for the other glycopep tide antibiotics of the vancomycin group that have been examined so fa r, binding of cell wall peptides and dimerization are cooperative. Res ults: Here we show that the two halves of the asymmetric homodimer for med by ristocetin A have different affinities for ligand binding, One of these sites is preferentially filled before the other, and binding to this site is cooperative with dimerization. Ligand binding to the o ther, less favored half of the dimer, is anti-cooperative with dimeriz ation. Conclusions: In dimer complexes, anti-cooperativity of dimeriza tion upon ligand binding can be a result of asymmetry, in which two bi nding sites have different affinities for ligands, Such a system, in w hich one binding site is filled preferentially, may be a mechanism by which the cooperativity between ligand binding and dimerization is fin e tuned and may thus have relevance to the control of signal transduct ion in biological systems.