Molecular basis for triclosan activity involves a flipping loop in the active site.

Area of Science:

• Biochemistry and structural biology
• Enzyme kinetics and inhibition

Background:

• Escherichia coli enoyl reductase is a crucial enzyme in fatty acid biosynthesis.
• Understanding its interaction with inhibitors like triclosan is vital for antimicrobial drug development.

Purpose of the Study:

• To determine the crystal structure of the Escherichia coli enoyl reductase-NAD+-triclosan complex.
• To elucidate the role of the Ile192-Ser198 loop in enzyme-inhibitor interactions.

Main Methods:

• X-ray crystallography at 2.5 A resolution.
• Analysis of protein-ligand and protein-cofactor interactions.

Main Results:

• The Ile192-Ser198 loop adopts a closed conformation, unlike in previous studies.
• This closed loop forms specific interactions with triclosan and the NAD+ cofactor.
• The loop's conformation is critical for triclosan's enhanced binding potency.

Conclusions:

• The dynamic Ile192-Ser198 loop plays a key role in substrate and ligand recognition.
• The closed loop conformation is essential for triclosan's high binding affinity.
• This finding provides a basis for structure-based design of novel enoyl reductase inhibitors.