title: Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus.
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.
authors.affiliation: Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Quanjiang
authors.initials: Q
authors.lastname: Ji
authors.affiliation: Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai 201203, China.
authors.forename: Guangrong
authors.initials: G
authors.lastname: Qin
authors.affiliation: Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Ziyang
authors.initials: Z
authors.lastname: Hao
authors.affiliation: Synchrotron Research Center, LS-CAT, Northwestern University, Argonne, Illinois 60439, USA.
authors.forename: Zdzislaw
authors.initials: Z
authors.lastname: Wawrzak
authors.affiliation: Indiana University School of Medicine-Northwest, Gary, Indiana 46408, USA.
authors.forename: Won-Sik
authors.initials: WS
authors.lastname: Yeo
authors.affiliation: High-Throughput Analysis Laboratory, Department of Molecular Biosciences, Center for Structural Genomics of Infectious Diseases, Northwestern University, Evanston, Illinois 60208, USA.
authors.forename: Jenny Winjing
authors.initials: JW
authors.lastname: Quang
authors.affiliation: Indiana University School of Medicine-Northwest, Gary, Indiana 46408, USA.
authors.forename: Hoonsik
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Guan-Zheng
authors.initials: GZ
authors.lastname: Luo
authors.affiliation: Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Xiaocheng
authors.initials: X
authors.lastname: Weng
authors.affiliation: Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Qiancheng
authors.initials: Q
authors.lastname: You
authors.affiliation: High-Throughput Analysis Laboratory, Department of Molecular Biosciences, Center for Structural Genomics of Infectious Diseases, Northwestern University, Evanston, Illinois 60208, USA.
authors.forename: Chi-Hao
authors.initials: CH
authors.lastname: Luan
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, 929 E 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Yang
authors.affiliation: Indiana University School of Medicine-Northwest, Gary, Indiana 46408, USA.
authors.forename: Taeok
authors.initials: T
authors.lastname: Bae
authors.affiliation: State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Kunqian
authors.initials: K
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: He
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism*; D001577:Benzophenones / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D001426:Bacterial Proteins; D001577:Benzophenones; D050505:Mutant Proteins; D054852:Small Molecule Libraries; C121479:2,4-dihydroxybenzophenone