7ALR

Crystal structure of TD1-gatorbulin1 complex

Summary for 7ALR

• Entry DOI: 10.2210/pdb7alr/pdb
• Descriptor: Tubulin alpha-1B chain, GLYCEROL, Tubulin beta-3 chain, ... (11 entities in total)
• Functional Keywords: tubulin, gatorbulin, antitumoral, microtubule, structural protein
• Biological source: synthetic construct; More
• Total number of polymer chains: 3
• Total formula weight: 121928.39

Authors

Oliva, M.A.,Diaz, J.F. (deposition date: 2020-10-07, release date: 2021-03-03, Last modification date: 2024-01-31)

Primary citation

Matthew, S.,Chen, Q.Y.,Ratnayake, R.,Fermaintt, C.S.,Lucena-Agell, D.,Bonato, F.,Prota, A.E.,Lim, S.T.,Wang, X.,Diaz, J.F.,Risinger, A.L.,Paul, V.J.,Oliva, M.A.,Luesch, H.
Gatorbulin-1, a distinct cyclodepsipeptide chemotype, targets a seventh tubulin pharmacological site.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: 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.

PubMed: 33619102
DOI: 10.1073/pnas.2021847118

Experimental method

X-RAY DIFFRACTION (1.93 Å)