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The Structure of MT189-Tubulin Complex Provides Insights into Drug Design
- Source :
- Letters in Drug Design & Discovery. 16:1069-1073
- Publication Year :
- 2019
- Publisher :
- Bentham Science Publishers Ltd., 2019.
-
Abstract
- Background: Drugs that interfere with microtubule dynamics are used widely in cancer chemotherapy. Microtubules are composed of αβ-tubulin heterodimers, and the colchicine binding site of tubulin is an important pocket for designing tubulin polymerization inhibitors. We have previously designed and synthesized a series of colchicine binding site inhibitors (CBSIs). However, these compounds showed no anticancer activity in vivo. Then, we have used a deconstruction approach to obtain a new derivative MT189, which showed in vivo anticancer activity. Methods: We crystallized a protein complex including two tubulins, one stathmin-like domain of RB3 and one tubulin tyrosine ligase, and soaked MT189 into the crystals. We collected the diffraction data and determined the tubulin-MT189 structure to 2.8 Å. Results: Here, we report the crystal structure of tubulin complexed with MT189, elucidate how the small-molecular agent binds to tubulin and inhibits microtubule assembly, and explain previous results of the structure-activity-relationship studies. Conclusion: The tubulin-MT189 complex structure reveals the interactions between this agent and tubulin and provides insights into the design of new derivatives targeting the colchicine binding site.
- Subjects :
- 0301 basic medicine
Drug
Tubulin complex
Chemistry
media_common.quotation_subject
Structural protein
Pharmaceutical Science
macromolecular substances
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
030220 oncology & carcinogenesis
Drug Discovery
Biophysics
Molecular Medicine
media_common
Subjects
Details
- ISSN :
- 15701808
- Volume :
- 16
- Database :
- OpenAIRE
- Journal :
- Letters in Drug Design & Discovery
- Accession number :
- edsair.doi...........a0ff8e9f225242ac76ce2c319a755506