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Effective tailor-made force field parameterization of the several Zn coordination environments in the puzzling FTase enzyme: opening the door to the full understanding of its elusive catalytic mechanism

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Abstract

Protein farnesyltransferase (FTase) is very promising anticancer drug target, with several drugs in advanced stages of clinical testing. However, in spite of the thrilling achievements in the development of farnesyltransferase inhibitors (FTIs) over the past few years, the farnesylation mechanism remains, to some degree, a mystery. This work reports the determination and validation of three sets of molecular mechanical parameters specifically tailored to accurately account for the very specific nature of the several Zn coordination spheres formed during the unclear catalytic pathway of this puzzling metalloenzyme, and built on the top of recent experimental and theoretical results that have dramatically changed the way how the farnesylation mechanism is perceived. Extensive validation studies with 14 FTase crystallographic structures, EXAFS data, DFT, and QM/MM theoretical calculations are presented.

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  1. REQUIMTE, Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007, Porto, Portugal

    Sérgio Filipe Sousa, Pedro Alexandrino Fernandes & Maria João Ramos

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  1. Sérgio Filipe Sousa
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  2. Pedro Alexandrino Fernandes
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  3. Maria João Ramos
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Correspondence to Maria João Ramos.

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Sousa, S.F., Fernandes, P.A. & Ramos, M.J. Effective tailor-made force field parameterization of the several Zn coordination environments in the puzzling FTase enzyme: opening the door to the full understanding of its elusive catalytic mechanism. Theor Chem Acc 117, 171–181 (2007). https://doi.org/10.1007/s00214-006-0170-9

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