Structural basis for drug resistance conferred by β-tubulin mutations: a molecular modeling study on native and mutated tubulin complexes with epothilone B

• Published in: Journal of biomolecular structure & dynamics 2015-12, Vol.33 (12), p.2530-2540
• Main Authors: Navarrete, Karen R., Alderete, Joel B., Jiménez, Verónica A.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Binding Sites; drug resistance; Drug Resistance, Neoplasm - genetics; epothilones; Epothilones - chemistry; Epothilones - metabolism; Epothilones - pharmacology; Humans; Ligands; Microtubules - chemistry; Microtubules - metabolism; molecular dynamics; Molecular Dynamics Simulation; Molecular Structure; Mutation; Protein Multimerization; Protein Structure, Secondary; Protein Structure, Tertiary; Thermodynamics; tubulin; Tubulin - chemistry; Tubulin - genetics; Tubulin - metabolism
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2015.1063455

Using molecular modeling, we have investigated the structure and dynamic properties of epothilone B-tubulin complexes with wild-type and mutated tubulin, aimed at identifying the molecular factors involved in the emergence of drug resistance induced by four protein mutations at Phe270Val, Thr274Ile, Arg282Gln, and Gln292Glu. Our results revealed that tubulin mutations render significant changes in the protein conformation in regions involved either in the binding of the ligand or in interdimer contacts that are relevant to the assembly of stable microtubules. In addition, point mutations induce drastic changes in the binding pose of the ligand and in the interaction networks responsible for the epothilone-tubulin association. Large ligand displacements inside the binding pocket and an overall decrease in the strength of drug-receptor polar contacts suggest a looser binding of the ligand in tubulin mutants. These results explain the loss of activity for epothilone B against cancer cells that contain tubulin mutants and provide valuable information to enhance the understanding of the atomic source of epothilones' activity, which can be helpful to conduct further research on the rational design of more potent therapeutic tubulin-binding agents.