5CA0

Crystal structure of T2R-TTL-Lexibulin complex

Summary for 5CA0

• Entry DOI: 10.2210/pdb5ca0/pdb
• Related: 5C8Y 5CA1 5CB4
• Descriptor: Tubulin alpha-1B chain, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, 1-ethyl-3-[2-methoxy-4-(5-methyl-4-{[(1S)-1-(pyridin-3-yl)butyl]amino}pyrimidin-2-yl)phenyl]urea, ... (13 entities in total)
• Functional Keywords: inhibitor, complex, tubulin, structural protein
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cytoplasm, cytoskeleton: Q2XVP4 F2Z5B2; Golgi apparatus : P63043
• Total number of polymer chains: 6
• Total formula weight: 265378.76

Authors

Wang, Y.,Yu, Y.,Chen, Q.,Yang, J. (deposition date: 2015-06-29, release date: 2015-11-04, Last modification date: 2024-03-20)

Primary citation

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., 283:102-111, 2016

PubMed Abstract: Microtubules are dynamic assemblies of αβ-tubulin heterodimers and have been recognized as highly attractive targets for cancer chemotherapy. A broad range of agents bind to tubulin and interfere with microtubule assembly. Despite having a long history of characterization, colchicine binding site inhibitors (CBSIs) have not yet reached the commercial phase as anti-cancer drugs to date. We determined the structures of tubulin complexed with a set of structurally diverse CBSIs (lexibulin, nocodazole, plinabulin and tivantinib), among which nocodazole and tivantinib are both binary-function inhibitors targeting cancer-related kinases and microtubules simultaneously. High resolution structures revealed the detailed interactions between these ligands and tubulin. Our results showed that the binding modes of the CBSIs were different from previous docking models, highlighting the importance of crystal structure information in structure-based drug design. A real structure-based pharmacophore was proposed to rationalize key common interactions of the CBSIs at the colchicine domain. Our studies provide a solid structural basis for developing new anti-cancer agents for the colchicine binding site.

PubMed: 26462166
DOI: 10.1111/febs.13555

Experimental method

X-RAY DIFFRACTION (2.501 Å)