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Issue 10, 2012
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Structural insights into the potential of 4-fluoroproline to modulate biophysical properties of proteins

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Abstract

The unnatural amino acid 4-fluoroproline (4-FPro) can be used to replace natural proline in peptides and proteins to alter their stability, conformation and folding behavior. Interestingly, the two diastereomers (4R)- and (4S)-FPro behave quite differently resulting for example in increased or decreased protein stabilities. The reasons for the observed, opposed properties seem to be very complex and are not well understood yet, especially as only one single X-ray structure of a 4-FPro-modified protein is available, so far. The crystal structure of the large fragment of Taq DNA polymerase reported here far exceeds the molecular mass and number of 4-FPro residues of previous studied proteins and sheds light on how 4-FPro influences complex protein frameworks. It turns out that all aspects of prolyl Cγ-fluorination have to be considered in a combined fashion to understand how they account for the induced differences in protein stability. The interplay of different effects based on newly formed interactions and on the conformational preferences of 4-FPro determines whether the accepted diastereomer stabilizes or destabilizes the target protein. Due to counterbalanced effects, 4-FPro seems to be a very promising tool to even modify the properties of large enzymes with a high number of Pro residues since mono-fluorination at multiple sites is well tolerated by the target protein. Notably, the replacement of Pro by 4-FPro apparently also led to an improved crystallization capability of the DNA polymerase.

Graphical abstract: Structural insights into the potential of 4-fluoroproline to modulate biophysical properties of proteins

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Publication details

The article was received on 30 Apr 2012, accepted on 07 Jun 2012 and first published on 13 Jun 2012


Article type: Edge Article
DOI: 10.1039/C2SC20545A
Citation: Chem. Sci., 2012,3, 2924-2931

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    Structural insights into the potential of 4-fluoroproline to modulate biophysical properties of proteins

    B. Holzberger, S. Obeid, W. Welte, K. Diederichs and A. Marx, Chem. Sci., 2012, 3, 2924
    DOI: 10.1039/C2SC20545A

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