4Y10

Trypsin in complex with with BPTI mutant (2S)-2-amino-4,4-difluorobutanoic acid

Summary for 4Y10

• Entry DOI: 10.2210/pdb4y10/pdb
• Related: 4Y0Y 4Y0Z 4Y11
• Descriptor: Cationic trypsin, Pancreatic trypsin inhibitor, SULFATE ION, ... (6 entities in total)
• Functional Keywords: hydrolase inhibitors, digestion, metal-binding, protease, secreted, serine protease, zymogen, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Bos taurus (Cattle); More
• Cellular location: Secreted, extracellular space: P00760; Secreted: P00974
• Total number of polymer chains: 2
• Total formula weight: 30840.50

Authors

Loll, B.,Ye, S.,Berger, A.A.,Muelow, U.,Alings, C.,Wahl, M.C.,Koksch, B. (deposition date: 2015-02-06, release date: 2015-06-24, Last modification date: 2023-11-15)

Primary citation

Ye, S.,Loll, B.,Berger, A.A.,Mulow, U.,Alings, C.,Wahl, M.C.,Koksch, B.
Fluorine teams up with water to restore inhibitor activity to mutant BPTI.
Chem Sci, 6:5246-5254, 2015

PubMed 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.

PubMed: 29449928
DOI: 10.1039/c4sc03227f

Experimental method

X-RAY DIFFRACTION (1.37 Å)