Articles | Volume 2, issue 2
https://doi.org/10.5194/mr-2-629-2021
https://doi.org/10.5194/mr-2-629-2021
Research article
 | 
13 Aug 2021
Research article |  | 13 Aug 2021

High-affinity tamoxifen analogues retain extensive positional disorder when bound to calmodulin

Lilia Milanesi, Clare R. Trevitt, Brian Whitehead, Andrea M. Hounslow, Salvador Tomas, Laszlo L. P. Hosszu, Christopher A. Hunter, and Jonathan P. Waltho

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Cited articles

Barbato, G., Ikura, M., Kay, L. E., Pastor, R. W., and Bax, A.: Backbone dynamics of calmodulin studied by N-15 relaxation using inverse detected 2-dimensional NMR-spectroscopy – the central helix is flexible, Biochemistry, 31, 5269–5278, https://doi.org/10.1021/bi00138a005, 1992. 
Brown, S. C., Weber, P. L., and Mueller, L.: Toward complete H-1-NMR spectra in proteins. J. Magn. Reson., 77, 166–169, https://doi.org/10.1016/0022-2364(88)90042-x, 1988. 
Brünger, A. T.: X-PLOR. Version 3.1: A system for X-ray crystallography and NMR, Yale University Press, New Haven, CT, USA,​​​​​​​ 1992. 
Byer, S. J., Eckert, J. M., Brossier, N. M., Clodfelder-Miller, B. J., Turk, A. N., Carroll, A. J., Kappes, J. C., Zinn, K. R., Prasain, J. K., and Carroll, S. L.: Tamoxifen inhibits malignant peripheral nerve sheath tumor growth in an estrogen receptor-independent manner, Neuro-Oncology, 13, 28–41, https://doi.org/10.1093/neuonc/noq146, 2011. 
Carroll, M. J., Gromova, A. V., Miller, K. R., Tang, H., Wang, X. S., Tripathy, A., Singleton, S. F., Collins, E. J., and Lee, A. L.: Direct detection of structurally resolved dynamics in a multiconformation receptor-ligand complex, J. Am. Chem. Soc., 133, 6422–6428, https://doi.org/10.1021/ja2005253, 2011. 
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Short summary
The overall aim of the study is to provide a basis from which to improve the ability of tamoxifen family drugs to reduce the activity of a secondary target protein, calmodulin, during tumour development. The main conclusion is that the binding of a tamoxifen analogue is quite unlike that of other anti-calmodulin compounds in that two drug molecules bring the two domains of calmodulin into close proximity, but they are not fixed in orientation relative to the protein.