Structural insights into the inhibition of bacterial RecA by naphthalene polysulfonated compounds

Ziyuan Zhou; Qing Pan; Xinchen Lv; Jing Yuan; Yang Zhang; Ming-Xia Zhang; Ming Ke; Xiao-Mei Mo; Yong-Li Xie; Yingxia Liu; Ting Chen; Mingchan Liang; Feng Yin; Lei Liu; Yiqing Zhou; Kun Qiao; Rui Liu; Zigang Li; Nai-Kei Wong

doi:10.1016/j.isci.2020.101952

Structural insights into the inhibition of bacterial RecA by naphthalene polysulfonated compounds

iScience. 2020 Dec 17;24(1):101952. doi: 10.1016/j.isci.2020.101952. eCollection 2021 Jan 22.

Authors

Ziyuan Zhou^{1

2}, Qing Pan³, Xinchen Lv^{4

5}, Jing Yuan², Yang Zhang⁶, Ming-Xia Zhang², Ming Ke⁷, Xiao-Mei Mo², Yong-Li Xie², Yingxia Liu², Ting Chen⁶, Mingchan Liang⁸, Feng Yin^{8

9}, Lei Liu², Yiqing Zhou¹⁰, Kun Qiao², Rui Liu^{4

5}, Zigang Li^{8

9}, Nai-Kei Wong^{1

2}

Affiliations

¹ Department of Pharmacology, Shantou University Medical College, Shantou 515041, China.
² National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, The Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen 518112, China.
³ Shenzhen Key Laboratory of Microbial Genetic Engineering, College of Life Sciences and Oceanology, Shenzhen University, Shenzhen 518055, China.
⁴ Key Laboratory of Molecular Design for Plant Cell Factory of Guangdong Higher Education Institutes, Institute of Plant and Food Science, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China.
⁵ National Key Laboratory of Plant Molecular Genetics & Shanghai Center for Plant Stress Biology, CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai 201602, China.
⁶ CAS Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, 164 West Xingang Road, Guangzhou 510301, China.
⁷ BGI-Shenzhen, Shenzhen 518083, China.
⁸ Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen 518055, China.
⁹ State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen 518055, China.
¹⁰ School of Biotechnology and Food Engineering, Changshu Institute of Technology, Changshu, Jiangsu 215500, China.

Abstract

As a promising target for alternative antimicrobials, bacterial recombinase A (RecA) protein has attracted much attention for its roles in antibiotic-driven SOS response and mutagenesis. Naphthalene polysulfonated compounds (NPS) such as suramin have previously been explored as antibiotic adjuvants targeting RecA, although the underlying structural bases for RecA-ligand interactions remain obscure. Based on our in silico predictions and documented activity of NPS in vitro, we conclude that the analyzed NPS likely interact with Tyr103 (Y103) and other key residues in the ATPase activity center (pocket A). For validation, we generated recombinant RecA proteins (wild-type versus Y103 mutant) to determine the binding affinities for RecA protein interactions with suramin and underexamined NPS in isothermal titration calorimetry. The corresponding dissociation constants (K _d) ranged from 11.5 to 18.8 μM, and Y103 was experimentally shown to be critical to RecA-NPS interactions.

Keywords: Biochemistry; Microbiology; Molecular Microbiology.