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

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 () and Chuan He ()
Additional contact information
Quanjiang Ji: and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago
Peter J. Chen: and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago
Guangrong Qin: State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Xin Deng: and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago
Ziyang Hao: and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago
Zdzislaw Wawrzak: Synchrotron Research Center, LS-CAT, Northwestern University
Won-Sik Yeo: Indiana University School of Medicine-Northwest
Jenny Winjing Quang: High-Throughput Analysis Laboratory, Center for Structural Genomics of Infectious Diseases, Northwestern University
Hoonsik Cho: Indiana University School of Medicine-Northwest
Guan-Zheng Luo: and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago
Xiaocheng Weng: and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago
Qiancheng You: and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago
Chi-Hao Luan: High-Throughput Analysis Laboratory, Center for Structural Genomics of Infectious Diseases, Northwestern University
Xiaojing Yang: University of Chicago
Taeok Bae: Indiana University School of Medicine-Northwest
Kunqian Yu: State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Hualiang Jiang: State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Chuan He: and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago

Nature Communications, 2016, vol. 7, issue 1, 1-11

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

Date: 2016
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DOI: 10.1038/ncomms11000

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