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

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. Lastly, 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:
 [1] ;  [1] ;  [2] ;  [1] ;  [1] ;  [3] ;  [4] ;  [5] ;  [4] ;  [1] ;  [1] ;  [1] ;  [5] ;  [6] ;  [4] ;  [2] ;  [2] ;  [1]
  1. The Univ. of Chicago, Chicago, IL (United States)
  2. Chinese Academy of Sciences, Shanghai (China)
  3. Northwestern Univ., Argonne, IL (United States)
  4. Indiana Univ. School of Medicine-Northwest, Gary, IN (United States)
  5. Northwestern Univ., Evanston, IL (United States)
  6. Univ. of Chicago, Chicago, IL (United States)
Publication Date:
OSTI Identifier:
1247346
Grant/Contract Number:
AC02-06CH11357
Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 7; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org:
USDOE Office of Science (SC)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES