Gatorbulin-1, a distinct cyclodepsipeptide chemotype, targets a seventh tubulin pharmacological site

Autor: María A. Oliva, Susan Matthew, Ranjala Ratnayake, Hendrik Luesch, Francesca Bonato, April L. Risinger, Andrea E. Prota, Daniel Lucena-Agell, Seok Ting Lim, Qi-Yin Chen, J. Fernando Díaz, Charles S. Fermaintt, Xiaomeng Wang, Valerie J. Paul
Přispěvatelé: National Cancer Institute (US), National Institute of General Medical Sciences (US), University of Florida, Ministerio de Ciencia e Innovación (España), Consejo Superior de Investigaciones Científicas (España), European Commission, Matthew, S. [0000-0003-4943-4777], Chen, Qi-Yin [0000-0002-4364-1057], Ratnayake, R. [0000-0002-5980-2070], Fermaintt, Charles S. [0000-0001-8140-5461], Lucena-Agell, Daniel [0000-0001-7198-2900], Bonato, Francesca [0000-0002-0579-2874], Prota, Andrea E. [0000-0003-0875-5339], Lim, Seok Ting [0000-0002-5173-5715], Wang, Xiaomeng [0000-0002-1036-2764], Díaz, José Fernando [0000-0003-2743-3319], Risinger, April L. [0000-0002-4363-3268], Paul, Valerie J. [0000-0002-4691-1569], Oliva, María A. [0000-0002-2215-4639], Luesch, H. [0000-0002-4091-7492], Matthew, S., Chen, Qi-Yin, Ratnayake, R., Fermaintt, Charles S., Lucena-Agell, Daniel, Bonato, Francesca, Prota, Andrea E., Lim, Seok Ting, Wang, Xiaomeng, Díaz, José Fernando, Risinger, April L., Paul, Valerie J., Oliva, María A., Luesch, H.
Rok vydání: 2021
Předmět:
Models
Molecular
Protein Conformation
alpha-Helical
Marine natural product
Antineoplastic Agents
Apoptosis
Total synthesis
Crystallography
X-Ray
Cyanobacteria
01 natural sciences
Pentapeptide repeat
Microtubules
03 medical and health sciences
chemistry.chemical_compound
Bacterial Proteins
Microtubule
Tubulin
Cell Line
Tumor
Depsipeptides
Drug Discovery
Humans
Maytansine
Protein Interaction Domains and Motifs
Binding site
Vinca Alkaloids
030304 developmental biology
0303 health sciences
Biological Products
Multidisciplinary
Natural product
Binding Sites
biology
Chemotype
010405 organic chemistry
Biological Sciences
HCT116 Cells
In vitro
Tubulin Modulators
3. Good health
0104 chemical sciences
chemistry
Biochemistry
Pyrones
biology.protein
Protein Conformation
beta-Strand
Taxoids
Colchicine
Protein Binding
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
instname
Proc Natl Acad Sci U S A
Popis: 35 p.-5 fig.-1 tab.
Tubulin-targeted chemotherapy has proven to be a successful and wide spectrum strategy against solid and liquid malignancies. Therefore, new ways to modulate this essential protein could lead to new antitumoral pharmacological approaches. Currently known tubulin agents bind to six distinct sites at α/β-tubulin either promoting microtubule stabilization or depolymerization. We have discovered a seventh binding site at the tubulin intradimer interface where a novel microtubule-destabilizing cyclodepsipeptide, termed gatorbulin-1 (GB1), binds. GB1 has a unique chemotype produced by a marine cyanobacterium. We have elucidated this dual, chemical and mechanistic, novelty through multidimensional characterization, starting with bioactivity-guided natural product isolation and multinuclei NMR-based structure determination, revealing the modified pentapeptide with a functionally critical hydroxamate group; and validation by total synthesis. We have investigated the pharmacology using isogenic cancer cell screening, cellular profiling, and complementary phenotypic assays, and unveiled the underlying molecular mechanism by in vitro biochemical studies and high-resolution structural determination of the α/β-tubulin−GB1 complex.
This research was supported by the NIH, National Cancer Institute Grants R01CA172310 (to H.L.) and R50CA211487 (to R.R.) and National Institute of General Medical Sciences Grant P41GM086210 (to H.L. and V.J.P.), Commercialization Fund Award from University of Florida (UF) Innovate (UF Office of Technology Licensing), and Debbie and Sylvia DeSantis Chair professorship (H.L.). The biochemical and the crystal structure work was supported by grants Ministerio de Ciencia e Innovación PID2019-10454RB-I00/AEI/10.13039/501100011033, Fondo de Investigaciones Sanitarias and COV20/01007E Proyecto Intramural Especial 201920E111 from Consejo Superior de Investigaciones Científicas (to J.F.D.) and European Union H2020-MSCA-ITN-2019 860070 TUBINTRAIN grant (to J.F.D. and A.E.P.).
Databáze: OpenAIRE
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