Interaction of the herbicide glyphosate with its target enzyme 5-enolpyvuvylshikimate 3-phosphate synthase in atomic detail

Biosynthesis of aromatic amino acids in plants, many bacteria, and microbes relies on the enzyme 5-enolpyruvylshikimate 3-phosphate (EPSP) synthase, a prime target for drugs and herbicides. We have identified the interaction of EPSP synthase with one of its two substrates (shikimate 3-phosphate) and with the widely used herbicide glyphosate by x-ray crystallography. The tw o-domain enzyme closes on ligand binding, thereby forming the active site i n the interdomain cleft. Glyphosate appears to occupy the binding site of t he second substrate of EPSP synthase (phosphoenol pyruvate), mimicking an i ntermediate state of the ternary enzyme-substrates complex. The elucidation of the active site of EPSP synthase and especially of the binding pattern of glyphosate provides a valuable roadmap for engineering new herbicides an d herbicide-resistant crops, as well as new antibiotic and antiparasitic dr ugs.