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Variations in the colchicine-binding domain provide insight into the structural switch of tubulin.

Dorléans A, Gigant B, Ravelli RB, Mailliet P, Mikol V, Knossow M
Proc Natl Acad Sci U S A 106 13775-9 (2009)
Related entries: 3hkc, 3hkd, 3hke

Cited: 122 times
EuropePMC logo PMID: 19666559

Abstract

Structural changes occur in the alphabeta-tubulin heterodimer during the microtubule assembly/disassembly cycle. Their most prominent feature is a transition from a straight, microtubular structure to a curved structure. There is a broad range of small molecule compounds that disturbs the microtubule cycle, a class of which targets the colchicine-binding site and prevents microtubule assembly. This class includes compounds with very different chemical structures, and it is presently unknown whether they prevent tubulin polymerization by the same mechanism. To address this issue, we have determined the structures of tubulin complexed with a set of such ligands and show that they interfere with several of the movements of tubulin subunits structural elements upon its transition from curved to straight. We also determined the structure of tubulin unliganded at the colchicine site; this reveals that a beta-tubulin loop (termed T7) flips into this site. As with colchicine site ligands, this prevents a helix which is at the interface with alpha-tubulin from stacking onto a beta-tubulin beta sheet as in straight protofilaments. Whereas in the presence of these ligands the interference with microtubule assembly gets frozen, by flipping in and out the beta-subunit T7 loop participates in a reversible way in the resistance to straightening that opposes microtubule assembly. Our results suggest that it thereby contributes to microtubule dynamic instability.

Reviews - 3hkb mentioned but not cited (2)

  1. Molecular interactions at the colchicine binding site in tubulin: An X-ray crystallography perspective. Wang J, Miller DD, Li W. Drug Discov Today 27 759-776 (2022)
  2. Computational Approaches to the Rational Design of Tubulin-Targeting Agents. Pérez-Peña H, Abel AC, Shevelev M, Prota AE, Pieraccini S, Horvath D. Biomolecules 13 285 (2023)

Articles - 3hkb mentioned but not cited (6)

  1. Variations in the colchicine-binding domain provide insight into the structural switch of tubulin. Dorléans A, Gigant B, Ravelli RB, Mailliet P, Mikol V, Knossow M. Proc Natl Acad Sci U S A 106 13775-13779 (2009)
  2. Mechanism of microtubule stabilization by taccalonolide AJ. Wang Y, Yu Y, Li GB, Li SA, Wu C, Gigant B, Qin W, Chen H, Wu Y, Chen Q, Yang J. Nat Commun 8 15787 (2017)
  3. The free energy profile of tubulin straight-bent conformational changes, with implications for microtubule assembly and drug discovery. Peng LX, Hsu MT, Bonomi M, Agard DA, Jacobson MP. PLoS Comput Biol 10 e1003464 (2014)
  4. How to deal with low-resolution target structures: using SAR, ensemble docking, hydropathic analysis, and 3D-QSAR to definitively map the αβ-tubulin colchicine site. Da C, Mooberry SL, Gupton JT, Kellogg GE. J Med Chem 56 7382-7395 (2013)
  5. A collective motion description of tubulin βT7 loop dynamics. Chattopadhyaya S, Chakravorty D, Basu G. Biophys Physicobiol 16 264-273 (2019)
  6. Biological activity and interaction mechanism of the diketopiperazine derivatives as tubulin polymerization inhibitors. Tian Z, Chu Y, Wang H, Zhong L, Deng M, Li W. RSC Adv 8 1055-1064 (2018)


Reviews citing this publication (13)

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Articles citing this publication (101)

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