Issue 9, 2015

Fluorine teams up with water to restore inhibitor activity to mutant BPTI

Abstract

Introducing fluorine into molecules has a wide range of effects on their physicochemical properties, often desirable but in most cases unpredictable. The fluorine atom imparts the C–F bond with low polarizability and high polarity, and significantly affects the behavior of neighboring functional groups, in a covalent or noncovalent manner. Here, we report that fluorine, present in the form of a single fluoroalkyl amino acid side chain in the P1 position of the well-characterized serine-protease inhibitor BPTI, can fully restore inhibitor activity to a mutant that contains the corresponding hydrocarbon side chain at the same site. High resolution crystal structures were obtained for four BPTI variants in complex with bovine β-trypsin, revealing changes in the stoichiometry and dynamics of water molecules in the S1 subsite. These results demonstrate that the introduction of fluorine into a protein environment can result in “chemical complementation” that has a significantly favorable impact on protein–protein interactions.

Graphical abstract: Fluorine teams up with water to restore inhibitor activity to mutant BPTI

Supplementary files

Article information

Article type
Edge Article
Submitted
21 Oct 2014
Accepted
11 Jun 2015
First published
12 Jun 2015
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2015,6, 5246-5254

Author version available

Fluorine teams up with water to restore inhibitor activity to mutant BPTI

S. Ye, B. Loll, A. A. Berger, U. Mülow, C. Alings, M. C. Wahl and B. Koksch, Chem. Sci., 2015, 6, 5246 DOI: 10.1039/C4SC03227F

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