The role of the B-ring of colchicine in the stability of the colchicine-tubulin complex.
The binding of colchicine to tubulin is a slow, temperature-dependent and a poorly reversible process. Colchicine analogues modified in the B-ring of colchicine have been reported to bind to tubulin fairly rapidly (Ray, K., Bhattacharyya, B. and Biswas, B.B. (1981) J. Biol. Chem. 256, 6241-6244). In an effort to test the role of the B-ring in the reversibility of the colchicine-tubulin binding reaction, we have studied the kinetics of dissociation of the drug-tubulin complex for two B-ring-modified colchicine analogues under conditions in which the association reaction was blocked with a 40-fold excess of podophyllotoxin. In both cases, the dissociation was biphasic. The off-rate constants were determined and the results strongly suggest that the B-ring part of colchicine is responsible for the stability of the drug-tubulin complex. The dissociation data have been explained in terms of a binding model in which the binding of colchicine to tubulin involves a three-subdomain interaction rather than the previously suggested two-subdomain model (Andreu, J.M. and Timasheff, S.N. (1982) Biochemistry 21, 534-543).
D003078:Colchicine / Q000031:analogs & derivatives / Q000378:metabolism*; D007700:Kinetics; D008968:Molecular Conformation; D011034:Podophyllotoxin / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D013696:Temperature; D014404:Tubulin / Q000378:metabolism*
D014404:Tubulin; D011034:Podophyllotoxin; D003078:Colchicine