The inhibitory mechanism of aurintricarboxylic acid targeting serine/threonine phosphatase Stp1 in Staphylococcus aureus: insights from molecular dynamics simulations

Authors: Ting-ting Liu1,2, Teng Yang3, Mei-na Gao1,2, Kai-xian Chen1,2, Song Yang3, Kun-qian Yu1,2, Hua-liang Jiang1,2,4
1 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Center for R&D of Fine Chemicals, Guizhou University, Guiyang 550025, China
4 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Correspondence to: Song Yang:, Kun-qian Yu:,
DOI: 10.1038/s41401-019-0216-x
Received: 11 October 2018
Accepted: 17 January 2019
Advance online: 22 February 2019


Serine/threonine phosphatase (Stp1) is a member of the bacterial Mg2+-or Mn2+- dependent protein phosphatase/protein phosphatase 2C family, which is involved in the regulation of Staphylococcus aureus virulence. Aurintricarboxylic acid (ATA) is a known Stp1 inhibitor with an IC50 of 1.03 μM, but its inhibitory mechanism has not been elucidated in detail because the Stp1–ATA cocrystal structure has not been determined thus far. In this study, we performed 400 ns molecular dynamics (MD) simulations of the apo–Stp1 and Stp1–ATA complex models. During MD simulations, the flap subdomain of the Stp1–ATA complex experienced a clear conformational transition from an open state to a closed state, whereas the flap domain of apo–Stp1 changed from an open state to a semi-open state. In the Stp1–ATA complex model, the hydrogen bond (H-bond) between D137 and N142 disappeared, whereas critical H-bond interactions were formed between Q160 and H13, Q160/R161 and ATA, as well as N162 and D198. Finally, four residues (D137, N142, Q160, and R161) in Stp1 were mutated to alanine and the mutant enzymes were assessed using phosphate enzyme activity assays, which confirmed their important roles in maintaining Stp1 activity. This study indicated the inhibitory mechanism of ATA targeting Stp1 using MD simulations and sheds light on the future design of allosteric Stp1 inhibitors.
Keywords: antimicrobial resistance; Staphylococcus aureus; serine/threonine phosphatase; aurintricarboxylic acid; molecular dynamics simulations; flap subdomain

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