Structural Changes, Biological Consequences, and Repurposing of Colchicine Site Ligands

Microtubule-targeting agents (MTAs) bind to one of several distinct sites in the tubulin dimer, the subunit of microtubules. The binding affinities of MTAs may vary by several orders of magnitude, even for MTAs that specifically bind to a particular site. The first drug binding site discovered in tubulin was the colchicine binding site (CBS), which has been known since the discovery of the tubulin protein. Although highly conserved throughout eukaryotic evolution, tubulins show diversity in their sequences between tubulin orthologs (inter-species sequence differences) and paralogs (intraspecies differences, such as tubulin isotypes). The CBS is promiscuous and binds to a broad range of structurally distinct molecules that can vary in size, shape, and affinity. This site remains a popular target for the development of new drugs to treat human diseases (including cancer) and parasitic infections in plants and animals. Despite the rich knowledge about the diversity of tubulin sequences and the structurally distinct molecules that bind to the CBS, a pattern has yet to be found to predict the affinity of new molecules that bind to the CBS. In this commentary, we briefly discuss the literature evidencing the coexistence of the varying binding affinities for drugs that bind to the CBS of tubulins from different species and within species. We also comment on the structural data that aim to explain the experimental differences observed in colchicine binding to the CBS of beta-tubulin class VI (TUBB1) compared to other isotypes.

Automated summary

Microtubule-targeting agents (MTAs) bind to specific sites in the subunit of microtubules. The colchicine binding site (CBS) is a common target for drugs to treat human diseases and parasitic infections. However, despite the diversity of tubulin sequences and the molecules that bind to CBS, there is currently no pattern to predict the affinity of new molecules. This commentary discusses the varying binding affinities of drugs that bind to CBS and explores structural data explaining experimental differences.