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In microorganisms and plants, N-acetyl-l-glutamate kinase (NAGK) catalyzes the second step in l-arginine synthesis, the phosphorylation of N-Acetyl-l-glutamate (NAG) to give N-acetyl-l-glutamate-5-phosphate. NAGK is only present in microorganisms and plants but absent in mammals, which makes it an attractive target for antimicrobial or biocidal development. Understanding the substrate binding mode and reaction mechanism of NAGK is crucial for targeting the kinase to develop potential therapies. Here, the substrate binding mode was studied by comparing the conformational change of NAGK in the presence and in the absence of the NAG substrate based on molecular dynamics simulations. We revealed that with substrate binding, the catalytic site of the kinase involving three loops in NAGK exhibits a closed conformation, which is predominantly controlled by an interaction between Arg98 and the α-COO^– of …