The Structure of MT189-Tubulin Complex Provides Insights into Drug Design

Author(s): Zhongping Li , Lingling Ma , Chengyong Wu , Tao Meng , Lanping Ma , Wenyue Zheng , Yamei Yu* , Qiang Chen* , Jinliang Yang , Jingkang Shen .

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 9 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


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.

Keywords: Crystal structure, tubulin, colchicine binding site, inhibitor, MT189, drug design.

[1]
Jordan, M.A.; Wilson, L. Microtubules as a target for anticancer drugs. Nat. Rev. Cancer, 2004, 4, 253-265.
[2]
Dorleans, A.; Gigant, B.; Ravelli, R.B.; Mailliet, P.; Mikol, V.; Knossow, M. Variations in the colchicine-binding domain provide insight into the structural switch of tubulin. Proc. Natl. Acad. Sci. USA, 2009, 106, 13775-13779.
[3]
Carneiro, T.R.; do Amaral, D.N.; Fokoue, H.H.; Sant’Anna, C.M.R.; Porras, M.L.G.; Oliveira, A.C.A.; Cavalcanti, B.C.; Pessoa, C.; Barreiro, E.J.; Lima, L.M. Synthesis, pharmacological evaluation and docking study of a new modulator of microtubule polymerization. Lett. Drug Des. Discov., 2018, 15, 778-786.
[4]
Wang, Y.; Zhang, H.; Gigant, B.; Yu, Y.; Wu, Y.; Chen, X.; Lai, Q.; Yang, Z.; Chen, Q.; Yang, J. Structures of a diverse set of colchicine binding site inhibitors in complex with tubulin provide a rationale for drug discovery. FEBS J., 2016, 283, 102-111.
[5]
Zhang, Z.; Meng, T.; He, J.; Li, M.; Tong, L.J.; Xiong, B.; Lin, L.; Shen, J.; Miao, Z.H.; Ding, J. MT7, a novel compound from a combinatorial library, arrests mitosis via inhibiting the polymerization of microtubules. Invest. New Drugs, 2010, 28, 715-728.
[6]
Zhang, Z.; Meng, T.; Yang, N.; Wang, W.; Xiong, B.; Chen, Y.; Ma, L.; Shen, J.; Miao, Z.H.; Ding, J. MT119, a new planar-structured compound, targets the colchicine site of tubulin arresting mitosis and inhibiting tumor cell proliferation. Int. J. Cancer, 2011, 129, 214-224.
[7]
Wang, W.; Wang, Y.Q.; Meng, T.; Yi, J.M.; Huan, X.J.; Ma, L.P.; Tong, L.J.; Chen, Y.; Ding, J.; Shen, J.K.; Miao, Z.H. MCL-1 degradation mediated by JNK activation via MEKK1/TAK1-MKK4 contributes to anticancer activity of new tubulin inhibitor MT189. Mol. Cancer Ther., 2014, 13, 1480-1491.
[8]
Xu, L.; Wang, W.; Meng, T.; Ma, L.P.; Tong, L.J.; Shen, J.K.; Wang, Y.Q.; Miao, Z.H. New microtubulin inhibitor MT189 suppresses angiogenesis via the JNK-VEGF/VEGFR2 signaling axis. Cancer Lett., 2018, 416, 57-65.
[9]
Charbaut, E.; Curmi, P.A.; Ozon, S.; Lachkar, S.; Redeker, V.; Sobel, A. Stathmin family proteins display specific molecular and tubulin binding properties. J. Biol. Chem., 2001, 276, 16146-16154.
[10]
Prota, A.E.; Bargsten, K.; Zurwerra, D.; Field, J.J.; Diaz, J.F.; Altmann, K.H.; Steinmetz, M.O. Molecular mechanism of action of microtubule-stabilizing anticancer agents. Science, 2013, 339, 587-590.
[11]
Minor, W.; Cymborowski, M.; Otwinowski, Z.; Chruszcz, M. HKL-3000: The integration of data reduction and structure solution-from diffraction images to an initial model in minutes. Acta Crystallogr. D Biol. Crystallogr., 2006, 62, 859-866.
[12]
Emsley, P.; Cowtan, K. Coot: Model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr., 2004, 60, 2126-2132.
[13]
Adams, P.D.; Afonine, P.V.; Bunkoczi, G.; Chen, V.B.; Davis, I.W.; Echols, N.; Headd, J.J.; Hung, L.W.; Kapral, G.J.; Grosse-Kunstleve, R.W.; McCoy, A.J.; Moriarty, N.W.; Oeffner, R.; Read, R.J.; Richardson, D.C.; Richardson, J.S.; Terwilliger, T.C.; Zwart, P.H. PHENIX: A comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr., 2010, 66, 213-221.
[14]
Chen, V.B.; Arendall, W.B. 3rd, Headd, J.J.; Keedy, D.A.; Immormino, R.M.; Kapral, G.J.; Murray, L.W.; Richardson, J.S.; Richardson, D.C. MolProbity: All-atom structure validation for macromolecular crystallography. Acta Crystallogr. D Biol. Crystallogr., 2010, 66, 12-21.
[15]
Ravelli, R.B.; Gigant, B.; Curmi, P.A.; Jourdain, I.; Lachkar, S.; Sobel, A.; Knossow, M. Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature, 2004, 428, 98-202.
[16]
An, W.; Wang, W.; Yu, T.; Zhang, Y.; Miao, Z.; Meng, T.; Shen, J. Discovery of novel 2-phenyl-imidazo [1,2-a]pyridine analogues targeting tubulin polymerization as antiproliferative agents. Eur. J. Med. Chem., 2016, 112, 367-372.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 9
Year: 2019
Page: [1069 - 1073]
Pages: 5
DOI: 10.2174/1570180816666181122122655
Price: $58

Article Metrics

PDF: 11
HTML: 2
EPUB: 1
PRC: 1