Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus

• DOI: 10.1038/ncomms11000
• Publication Date: 2016-03-18T07:25:32Z
• Authors: Quanjiang Ji; Peter J. Chen; Guangrong Qin; Xin Deng; Ziyang Hao; Zdzislaw Wawrzak; Won-Sik Yeo; Jenny Winjing Quang; Hoonsik Cho; Guan-Zheng Luo; Xiaocheng Weng; Qiancheng You; Chi-Hao Luan; Xiaojing Yang; Taeok Bae; Kunqian Yu; Hualiang Jiang; Chuan He
• Keywords: Staphylococcus aureus; Transcription, Genetic; Science; Q; Gene Expression Regulation, Bacterial; Crystallography, X-Ray; Article; Protein Structure, Tertiary; 3. Good health; Small Molecule Libraries; Benzophenones; Bacterial Proteins; Mutation; Mutant Proteins; Signal Transduction

Abstract Most low GC Gram-positive bacteria possess an essential walKR two-component system (TCS) for signal transduction involved in regulating cell wall homoeostasis. Despite the well-established intracellular regulatory mechanism, role of this TCS extracellular recognition and factors that modulate activity remain largely unknown. Here we identify receptor kinase ‘WalK’ (erWalK) as a key hub bridging input modulation Staphylococcus aureus . Characterization crystal structure erWalK revealed canonical Per-Arnt-Sim (PAS) domain sensing. Single amino-acid mutation potential signal-transduction residues resulted severely impaired function WalKR. A small molecule derived from structure-based virtual screening against is capable selectively activating TCS. The molecular level characterization will not only facilitate exploration natural signal(s) but also provide template rational design inhibitors.