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Structural rationale for the cross-resistance of tumor cells bearing the A399V variant of elongation factor eEF1A1 to the structurally unrelated didemnin B, ternatin, nannocystin A and ansatrienin B

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Abstract

At least four classes of structurally distinct natural products with potent antiproliferative activities target the translation elongation factor eEF1A1, which is best known as the G-protein that delivers amino acyl transfer RNAs (aa-tRNAs) to ribosomes during mRNA translation. We present molecular models in atomic detail that provide a common structural basis for the high-affinity binding of didemnin B, ternatin, ansatrienin B and nannocystin A to eEF1A1, as well as a rationale based on molecular dynamics results that accounts for the deleterious effect of replacing alanine 399 with valine. The proposed binding site, at the interface between domains I and III, is eminently hydrophobic and exists only in the GTP-bound conformation. Drug binding at this site is expected to disrupt neither loading of aa-tRNAs nor GTP hydrolysis but would give rise to stabilization of this particular conformational state, in consonance with reported experimental findings. The experimental solution of the three-dimensional structure of mammalian eEF1A1 has proved elusive so far and the highly homologous eEF1A2 from rabbit muscle has been crystallized and solved only as a homodimer in a GDP-bound conformation. Interestingly, in this dimeric structure the large interdomain cavity where the drugs studied are proposed to bind is occupied by a mostly hydrophobic α-helix from domain I of the same monomer. Since binding of this α-helix and any of these drugs to domain III of eEF1A(1/2) is, therefore, mutually exclusive and involves two distinct protein conformations, one intriguing possibility that emerges from our study is that the potent antiproliferative effect of these natural products may arise not only from inhibition of protein synthesis, which is the current dogma, but also from interference with some other non-canonical functions. From this standpoint, this type of drugs could be considered antagonists of eEF1A1/2 oligomerization, a hypothesis that opens up novel areas of research.

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Abbreviations

eEF1A:

Eukaryotic elongation factor 1A

uMD:

Unrestrained molecular dynamics

MM-ISMSA:

Molecular mechanics implicit solvent model surface area

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Acknowledgements

We are grateful to Prof. Antonio Jiménez-Ruiz for many fruitful discussions and help with the StatGraphics program.

Funding

Financial support from the Spanish Ministerio de Economía y Competitividad [SAF2015-64629-C2-2-R], Comunidad Autónoma de Madrid [BIPEDD-2-CM Project, ref. S-2010/BMD-2457], and PharmaMar S.A.U. is gratefully acknowledged.

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  1. Pedro A. Sánchez-Murcia

    Present address: Institute of Theoretical Chemistry, University of Vienna, Währinger Str. 17, 1090, Vienna, Austria

  2. Álvaro Cortés-Cabrera

    Present address: Computational Chemistry-UK, RD Platform Technology & Science, GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK

Authors and Affiliations

  1. Area of Pharmacology, Department of Biomedical Sciences and “Unidad Asociada IQM-CSIC”, School of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, 28805, Madrid, Spain

    Pedro A. Sánchez-Murcia, Álvaro Cortés-Cabrera & Federico Gago

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Contributions

Participated in research design: PAS, ACC, and FG. Conducted experiments: PAS and FG. Contributed new analytic tools: ACC. Performed data analysis: PAS, ACC, and FG. Wrote or contributed to the writing of the manuscript: PAS, ACC, and FG.

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Correspondence to Federico Gago.

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This work is dedicated to Prof. Manuel Feria (Department of Pharmacology, University of La Laguna, Santa Cruz de Tenerife, Spain) on occasion of his retirement.

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Sánchez-Murcia, P.A., Cortés-Cabrera, Á. & Gago, F. Structural rationale for the cross-resistance of tumor cells bearing the A399V variant of elongation factor eEF1A1 to the structurally unrelated didemnin B, ternatin, nannocystin A and ansatrienin B. J Comput Aided Mol Des 31, 915–928 (2017). https://doi.org/10.1007/s10822-017-0066-x

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