Chapter 2 : Two-Component Signal Transduction and Chemotaxis

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This chapter provides a review of the architecture and structures of histidine kinases (HKs) and response regulators (RRs) and a description of a well-characterized two component system, the bacterial chemotaxis signaling pathway. In addition, the potential of two-component systems as drug targets and the progress that has been made with inhibitor design and development are discussed. Two-component signal transduction systems are structured around two conserved proteins: an HK and an RR. An important area of research focuses on understanding how phosphorylation of the conserved regulatory domain affects the activities of the structurally and functionally diverse effector domains. Chemotaxis proteins were among the first HK and RRs for which biochemical activities were defined and for which three-dimensional structures were determined. In the enteric bacterium , the chemotaxis signaling pathway controls the direction of flagellar rotation; counterclockwise flagellar rotation produces smooth-swimming behavior, and clockwise rotation produces tumbling, allowing reorientation. CheB, which demethylates the chemotaxis receptors, is the primary locus of regulation. The emergence of multiple drug resistance is an increasing problem. The chapter discusses several classes of two-component systems that are attractive drug targets. Two-component regulatory systems are involved in many aspects of motility, including the regulation of expression of genes encoding the motility apparatus and chemotaxis. The well-conserved CheA-CheY-CheB components that mediate chemotaxis are discussed. The chapter describes the results of chemical library screening and initial attempts at rational design of inhibitors.

Citation: Lubetsky J, Stock A. 2005. Two-Component Signal Transduction and Chemotaxis, p 17-36. In Waksman G, Caparon M, Hultgren S (ed), Structural Biology of Bacterial Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555818395.ch2

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Two-Component Signal Transduction Systems
Nuclear Magnetic Resonance Spectroscopy
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Figure 1.

Schematic diagram of bacterial chemotaxis signal transduction. External stimuli trigger changes in protein modifications and protein-protein interactions that lead to behavioral responses generated by the flagellar motors, as described in the text. The proteins present in the chemotaxis system are shown as circles. CheC, CheD, and CheV (squares) are absent in but are present in a large number of other bacteria.

Citation: Lubetsky J, Stock A. 2005. Two-Component Signal Transduction and Chemotaxis, p 17-36. In Waksman G, Caparon M, Hultgren S (ed), Structural Biology of Bacterial Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555818395.ch2
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1. Anand, G. S.,, P. N. Goudreau,, and A. M. Stock. 1998. Activation of methylesterase CheB: evidence of a dual role for the regulatory domain. Biochemistry 37:1403814047.
2. Anand, G. S.,, and A. M. Stock. 2002. Kinetic basis for the stimulatory effect of phosphorylation on the methylesterase activity of CheB. Biochemistry 41:67526760.
3. Baikalov, I.,, I. Schröder,, M. Kaczor-Grzeskowiak,, D. Cascio,, R. P. Gunsalus,, and R. E. Dickerson. 1998. NarL dimerization? Suggestive evidence from a new crystal form. Biochemistry 37:36653676.
4. Baikalov, I.,, I. Schröder,, M. Kaczor-Grzeskowiak,, K. Grzeskowiak,, R. P. Gunsalus,, and R. E. Dickerson. 1996. Structure of the Escherichia coli response regulator NarL. Biochemistry 35:1105311061.
5. Barrett, J. F.,, R. M. Goldschmidt,, L. E. Lawrence,, B. Foleno,, R. Chen,, J. P. Demers,, S. Johnson,, R. Kanojia,, J. Fernandez,, J. Bernstein,, L. Licata,, A. Donetz,, S. Huang,, D. J. Hlasta,, M. J. Macielag,, K. Ohemeng,, R. Frechette,, M. B. Frosco,, D. H. Klaubert,, J. M. Whiteley,, L. Wang,, and J. A. Hoch. 1998. Antibacterial agents that inhibit two-component signal transduction systems. Proc. Natl. Acad. Sci. USA 95:53175322.
6. Barrett, J. F.,, and J. A. Hoch. 1998. Two-component signal transduction as a target for microbial anti-infective therapy. Antimicrob. Agents Chemother. 42:15291536.
7. Beier, D.,, and R. Frank. 2000. Molecular characterization of two-component systems of Helicobacter pylori. J. Bacteriol. 182:20682076.
8. Besant, P. G.,, M. V. Lasker,, C. D. Bui,, and C. W. Turck. 2002. Inhibition of branched-chain alpha-keto acid dehydrogenase kinase and Sln1 yeast histidine kinase by the antifungal antibiotic radicicol. Mol. Pharmacol. 62:289296.
9. Bilwes, A. M.,, L. A. Alex,, B. R. Crane,, and M. I. Simon. 1999. Structure of CheA, a signal-transducing histidine kinase. Cell 96:131141.
10. Bilwes, A. M.,, C. M. Quezada,, L. R. Croal,, B. R. Crane,, and M. I. Simon. 2001. Nucleotide binding by the histidine kinase CheA. Nat. Struct. Biol. 8:353360.
11. Birck, C.,, L. Mourey,, P. Gouet,, B. Fabry,, J. Schumacher,, P. Rousseau,, D. Kahn,, and J.-P. Samama. 1999. Conformational changes induced by phosphorylation of the FixJ receiver domain. Struct. Fold. Des. 7:15051515.
12. Boukhvalova, M.,, R. VanBruggen,, and R. C. Stewart. 2002. CheA kinase and chemoreceptor interaction surfaces on CheW. J. Biol. Chem. 277:2359623603.
13. Bourret, R. B.,, and A. M. Stock. 2002. Molecular information processing: lessons from bacterial chemotaxis. J. Biol. Chem. 277:96259628.
14. Bren, A.,, and M. Eisenbach. 2000. How signals are heard during bacterial chemotaxis: protein-protein interactions in sensory signal propagation. J. Bacteriol. 182:68656873.
15. Buckler, D. R.,, Y. Zhou,, and A. M. Stock. 2002. Evidence of intradomain and interdomain flexibility in an OmpR/PhoB homolog from Thermotoga maritima. Structure 10:153164.
16. Cai, S. J.,, A. Khorchid,, M. Ikura,, and M. Inouye. 2003. Probing catalytically essential domain orientation in histidine kinase EnvZ by targeted disulfide crosslinking. J. Mol. Biol. 328:409418.
17. Chang, C.,, and R. C. Stewart. 1998. The two-component system. Regulation of diverse signaling pathways in prokaryotes and eukaryotes. Plant Physiol. 117:723731.
18. Cho, H. S.,, S. Y. Lee,, D. Yan,, X. Pan,, J. S. Parkinson,, S. Kustu,, D. E. Wemmer,, and J. G. Pelton. 2000. NMR structure of activated CheY. J. Mol. Biol. 297:543551.
19. Da Re, S.,, J. Schumacher,, P. Rousseau,, J. Fourment,, C. Ebel,, and D. Kahn. 1999. Phosphorylation-induced dimerization of the FixJ receiver domain. Mol. Microbiol. 34:504511.
20. Djordjevic, S.,, P. N. Goudreau,, Q. Xu,, A. M. Stock,, and A. H. West. 1998. Structural basis for methylesterase CheB regulation by a phosphorylation-activated domain. Proc. Natl. Acad. Sci. USA 95:13811386.
21. Djordjevic, S.,, and A. M. Stock. 1998. Chemotaxis receptor recognition by methyltransferase CheR. Nat. Struct. Biol. 5:446450.
22. Djordjevic, S.,, and A. M. Stock. 1997. Crystal structure of the chemotaxis receptor methyltransferase CheR suggests a conserved structural motif for binding S-adenosylmethionine. Structure 5:545558.
23. Domagala, J. M.,, D. Alessi,, M. Cummings,, S. Gracheck,, L. Huang,, M. Huband,, G. Johnson,, E. Olson,, M. Shapiro,, R. Singh,, Y. Song,, R. Van Bogelen,, D. Vo,, and S. Wold. 1998. Bacterial two-component signalling as a therapeutic target in drug design. Inhibition of NRII by the diphenolic methanes (bisphenols). Adv. Exp. Med. Biol. 456:269286.
24. Ellison, D. W.,, and W. R. McCleary. 2000. The unphosphorylated receiver domain of PhoB silences the activity of its output domain. J. Bacteriol. 182:65926597.
25. Fabret, C.,, and J. A. Hoch. 1998. A two-component signal transduction system essential for growth of Bacillus subtilis: implications for anti-infective therapy. J. Bacteriol. 180:63756383.
26. Falke, J. J.,, and G. L. Hazelbauer. 2001. Transmembrane signaling in bacterial chemoreceptors. Trends Biochem. Sci. 26:257265.
27. Feng, J.,, M. R. Atkinson,, W. McCleary,, J. B. Stock,, B. L. Wanner,, and A. J. Ninfa. 1992. Role of phosphorylated metabolic intermediates in the regulation of glutamine synthetase synthesis in Escherichia coli. J. Bacteriol. 174:60616070.
28. Fiedler, U.,, and V. Weiss. 1995. A common switch in activation of the response regulators NtrC and PhoB: phosphorylation induces dimerization of the receiver modules. EMBO J. 14:36963705.
29. Fisher, S. L.,, W. Jiang,, B. L. Wanner,, and C. T. Walsh. 1995. Cross-talk between the histidine protein kinase VanS and the response regulator PhoB. J. Biol. Chem. 270:2314323149.
30. Fukuchi, K.,, Y. Kasahara,, K. Asai,, K. Kobayashi,, S. Moriya,, and N. Ogasawara. 2000. The essential twocomponent regulatory system encoded by yycF and yycG modulates expression of the ftsAZ operon in Bacillus subtilis. Microbiology 146:15731583.
31. Griswold, I. J.,, H. Zhou,, R. V. Swanson,, L. P. McIntosh,, M. I. Simon,, and F. W. Dahlquist. 2002. The solution structure and interactions of CheW from Thermotoga maritima. Nat. Struct. Biol. 9:121125.
32. Grohmann, E.,, G. Muth,, and M. Espinosa. 2003. Conjugative plasmid transfer in gram-positive bacteria. Microbiol. Mol. Biol. Rev. 67:277301.
33. Hakenbeck, R.,, T. Grebe,, D. Zahner,, and J. B. Stock. 1999. β-Lactam resistance in Streptococcus pneumoniae: penicillin-binding proteins and non-penicillin-binding proteins. Mol. Microbiol. 33:673678.
34. Halkides, C. J.,, M. M. McEvoy,, E. Casper,, P. Matsumura,, K. Volz,, and F. W. Dahlquist. 2000. The 1.9 Å resolution crystal structure of phosphono-CheY, an analogue of the active form of the response regulator, CheY. Biochemistry 39:52805286.
35. Hilliard, J. J.,, R. M. Goldschmidt,, L. Licata,, E. Z. Baum,, and K. Bush. 1999. Multiple mechanisms of action for inhibitors of histidine protein kinases from bacterial two-component systems. Antimicrob. Agents Chemother. 43:16931699.
36. Hlasta, D. J.,, J. P. Demers,, B. D. Foleno,, S. A. Fraga-Spano,, J. Guan,, J. J. Hillard,, M. J. Macielag,, K. A. Ohemeng,, C. M. Sheppard,, Z. Sui,, G. C. Webb,, M. A. Weidner-Wells,, H. Werblood,, and J. F. Barret. 1998. Novel inhibitors of bacterial two-component systems with gram positive antibacterial activity: pharmacophore identification based on the screening hit closantel. Bioorg. Med. Chem. Lett. 8:19231928.
37. Hoch, J. A.,, and T. J. Silhavy (ed.). 1995. Two-Component Signal Transduction. ASM Press, Washington, D.C.
38. Ikegami, T.,, T. Okada,, I. Ohki,, J. Hirayama,, T. Mizuno,, and M. Shirakawa. 2001. Solution structure and dynamic character of the histidine-containing phosphotransfer domain of anaerobic sensor kinase ArcB from Escherichia coli. Biochemistry 40:375386.
39. Inouye, M.,, and R. Dutta (ed.). 2003. Histidine Kinases in Signal Transduction. Academic Press, Inc., San Diego, Calif.
40. Ishige, K.,, S. Nagasawa,, S. Tokishita,, and T. Mizuno. 1994. A novel device of bacterial signal transducers. EMBO J. 13:51955202.
41. Jacobs, C.,, I. J. Domian,, J. R. Maddock,, and L. Shapiro. 1999. Cell cycle-dependent polar localization of an essential bacterial histidine kinase that controls DNA replication and cell division. Cell 97:111120.
42. Jeon, Y.,, Y. S. Lee,, J. S. Han,, J. B. Kim,, and D. S. Hwang. 2001. Multimerization of phosphorylated and nonphosphorylated ArcA is necessary for the response regulator function of the Arc two-component signal transduction system. J. Biol. Chem. 276:4087340879.
43. Ji, G.,, R. Beavis,, and R. P. Novick. 1997. Bacterial interference caused by autoinducing peptide variants. Science 276:20272030.
44. Ji, G.,, R. C. Beavis,, and R. P. Novick. 1995. Cell density control of staphylococcal virulence mediated by an octapeptide pheromone. Proc. Natl. Acad. Sci. USA 92:1205512059.
45. Josenhans, C.,, and S. Suerbaum. 2002. The role of motility as a virulence factor in bacteria. Int. J. Med. Microbiol. 291:605614.
46. Kanojia, R. K.,, W. Murray,, J. Bernstein,, J. Fernandez,, B. D. Foleno,, H. Krause,, L. Lawrence,, G. Webb,, and J. F. Battett. 1999. 6-Oxa isosteres of anacardic acids as potent inhibitors of bacterial histidine protein kinase (HPK)-mediated two-component regulatory systems. Bioorg. Med. Chem. Lett. 9:29472952.
47. Karatan, E.,, M. M. Saulmon,, M. W. Bunn,, and G. W. Ordal. 2001. Phosphorylation of the response regulator CheV is required for adaptation to attractants during Bacillus subtilis chemotaxis. J. Biol. Chem. 276:4361843626.
48. Kern, D.,, B. F. Volkman,, P. Luginbuhl,, M. J. Nohaile,, S. Kustu,, and D. E. Wemmer. 1999. Structure of a transiently phosphorylated switch in bacterial signal transduction. Nature 40:894898.
49. Kim, K. K.,, H. Yokota,, and S.-H. Kim. 1999. Four-helical-bundle structure of the cytoplasmic domain of a serine chemotaxis receptor. Nature 400:787792.
50. Kirby, J. R.,, C. J. Kristich,, M. M. Saulmon,, M. A. Zimmer,, L. F. Garrity,, I. B. Zhulin,, and G. W. Ordal. 2001. CheC is related to the family of flagellar switch proteins and acts independently from CheD to control chemotaxis in Bacillus subtilis. Mol. Microbiol. 42:573585.
51. Kondo, H.,, A. Nakagawa,, J. Nishihira,, Y. Nishimura,, T. Mizuno,, and I. Tanaka. 1997. Escherichia coli positive regulator OmpR has a large loop structure at the putative RNA polymerase interaction site. Nat. Struct. Biol. 4:2831.
52. Kristich, C. J.,, and G. W. Ordal. 2002. Bacillus subtilis CheD is a chemoreceptor modification enzyme required for chemotaxis. J. Biol. Chem. 277:2535625362.
53. Lewis, R. J.,, J. A. Brannigan,, K. Muchová,, I. Barák,, and A. J. Wilkinson. 1999. Phosphorylated aspartate in the structure of a response regulator protein. J. Mol. Biol. 294:915.
54. Li, J.,, R. V. Swanson,, M. I. Simon,, and R. M. Weis. 1995. The response regulators CheB and CheY exhibit competitive binding to the kinase CheA. Biochemistry 34:1462614636.
55. Lukat, G. S.,, W. R. McCleary,, A. M. Stock,, and J. B. Stock. 1992. Phosphorylation of bacterial response regulator proteins by low molecular weight phospho-donors. Proc. Natl. Acad. Sci. USA 89:718722.
56. Lyon, G. J.,, P. Mayville,, T. W. Muir,, and R. P. Novick. 2000. Rational design of a global inhibitor of the virulence response in Staphylococcus aureus, based in part on localization of the site of inhibition to the receptorhistidine kinase, AgrC. Proc. Natl. Acad. Sci. USA 97:1333013335.
57. Lyon, G. J.,, J. S. Wright,, A. Christopoulos,, R. P. Novick,, and T. W. Muir. 2002. Reversible and specific extracellular antagonism of receptor-histidine kinase signaling. J. Biol. Chem. 277:62476253.
58. Macielag, M. J.,, J. P. Demers,, S. A. Fraga-Spano,, D. J. Hlasta,, S. G. Johnson,, R. M. Kanojia,, R. K. Russell,, Z. Sui,, M. A. Weidner-Wells,, H. Werblood,, B. D. Foleno,, R. M. Goldschmidt,, M. J. Loeloff,, G. C. Webb,, and J. F. Barrett. 1998. Substituted salicylanilides as inhibitors of two-component regulatory systems in bacteria. J. Med. Chem. 41:29392945.
59. Macielag, M. J.,, and R. Goldschmidt. 2000. Inhibitors of bacterial two-component signalling systems. Expert Opin. Investig. Drugs 9:23512369.
60. Maddock, J. R.,, and L. Shapiro. 1993. Polar location of the chemoreceptor complex in the Escherichia coli cell. Science 259:17171723.
61. Maris, A. E.,, M. R. Sawaya,, M. Kaczor-Grzeskowiak,, M. R. Jarvis,, S. M. Bearson,, M. L. Kopka,, I. Schroder,, R. P. Gunsalus,, and R. E. Dickerson. 2002. Dimerization allows DNA target site recognition by the NarL response regulator. Nat. Struct. Biol. 9:771778.
62. Martin, P. K.,, T. Li,, D. Sun,, D. P. Biek,, and M. B. Schmid. 1999. Role in cell permeability of an essential twocomponent system in Staphylococcus aureus. J. Bacteriol. 181:36663673.
63. Martinez-Hackert, E.,, and A. M. Stock. 1997. The DNA-binding domain of OmpR: crystal structure of a winged-helix transcription factor. Structure 5:109124.
64. Matsushita, M.,, and K. D. Janda. 2002. Histidine kinases as targets for new antimicrobial agents. Bioorg. Med. Chem. 10:866867.
65. Mayville, P.,, G. Ji,, R. Beavis,, H. Yang,, M. Goger,, R. P. Novick,, and T. W. Muir. 1999. Structure-activity analysis of synthetic autoinducing thiolactone peptides from Staphylococcus aureus responsible for virulence. Proc. Natl. Acad. Sci. USA 96:12181223.
66. McCleary, W. R. 1996. The activation of PhoB by acetylphosphate. Mol. Microbiol. 20:11551163.
67. McCleary, W. R.,, and J. B. Stock. 1994. Acetyl phosphate and the activation of two-component response regulators. J. Biol. Chem. 269:3156731572.
68. McCleary, W. R.,, J. B. Stock,, and A. J. Ninfa. 1993. Is acetyl phosphate a global signal in Escherichia coli? J. Bacteriol. 175:27932798.
69. McDevitt, D.,, D. J. Payne,, D. J. Holmes,, and M. Rosenberg. 2002. Novel targets for the future development of antibacterial agents. J. Appl. Microbiol. 92:28S34S.
70. McEvoy, M. M.,, A. C. Hausrath,, G. B. Randolph,, S. J. Remington,, and F. W. Dahlquist. 1998. Two binding modes reveal flexibility in kinase/response regulator interactions in the bacterial chemotaxis pathway. Proc. Natl. Acad. Sci. USA 95:73337338.
71. McEvoy, M. M.,, D. R. Muhandiram,, L. E. Kay,, and F. W. Dahlquist. 1996. Structure and dynamics of a CheY-binding domain of the chemotaxis kinase CheA determined by nuclear magnetic resonance spectroscopy. Biochemistry 35:56335640.
72. Miller, M. B.,, and B. L. Bassler. 2001. Quorum sensing in bacteria. Annu. Rev. Microbiol. 55:165199.
73. Mizuno, T. 1997. Compilation of all genes encoding two-component phosphotransfer signal transducers in the genome of Escherichia coli. DNA Res. 4:161168.
74. Ninfa, E. G.,, M. R. Atkinson,, E. S. Kamberov,, and A. J. Ninfa. 1993. Mechanism of autophosphorylation of Escherichia coli nitrogen regulator II (NRII or NtrB): trans-phosphorylation between subunits. J. Bacteriol. 175:70247032.
75. Park, S. Y.,, X. Chao,, G. Gonzalez-Bonet,, B. D. Beel,, A. M. Bilwes,, and B. R. Crane. 2004. Structure and function of an unusual family of protein phosphatases: the bacterial chemotaxis proteins CheC and CheX. Mol. Cell 16:563574.
76. Pelton, J. G.,, S. Kustu,, and D. E. Wemmer. 1999. Solution structure of the DNA-binding domain of NtrC with three alanine substitutions. J. Mol. Biol. 292:10951110.
77. Quon, K. C.,, G. T. Marczynski,, and L. Shapiro. 1996. Cell cycle control by an essential bacterial twocomponent signal transduction protein. Cell 84:8393.
78. Robinson, V. L.,, D. R. Buckler,, and A. M. Stock. 2000. A tale of two components: a novel kinase and a regulatory switch. Nat. Struct. Biol. 7:628633.
79. Robinson, V. L.,, T. Wu,, and A. M. Stock. 2003. Structural analysis of the domain interface in DrrB, a response regulator of the OmpR/PhoB subfamily. J. Bacteriol. 185:41864194.
80. Rosario, M. M.,, J. R. Kirby,, D. A. Bochar,, and G. W. Ordal. 1995. Chemotactic methylation and behavior in Bacillus subtilis: role of two unique proteins, CheC and CheD. Biochemistry 34:38233831.
81. Rosario, M. M. L.,, and G. W. Ordal. 1996. CheC and CheD interact to regulate methylation of Bacillus subtilis methyl-accepting chemotaxis proteins. Mol. Microbiol. 21:511518.
82. Roychoudhury, S.,, N. A. Zielinski,, A. J. Ninfa,, N. E. Allen,, L. N. Jungheim,, T. I. Nicas,, and A. M. Chakrabarty. 1993. Inhibitors of two-component signal transduction systems: inhibition of alginate gene activation in Pseudomonas aeruginosa. Proc. Natl. Acad. Sci. USA 90:965969.
83. Segall, J. E.,, S. M. Block,, and H. C. Berg. 1986. Temporal comparisons in bacterial chemotaxis. Proc. Natl. Acad. Sci. USA 83:89878991.
84. Song, H. K.,, J. Y. Lee,, M. G. Lee,, J. Moon,, K. Min,, J. K. Yang,, and S. W. Suh. 1999. Insights into eukaryotic multistep phosphorelay signal transduction revealed by the crystal structure of Ypd1p from Saccharomyces cerevisiae. J. Mol. Biol. 293:753761.
85. Stephenson, K.,, and J. A. Hoch. 2002. Virulence- and antibiotic resistance-associated two-component signal transduction systems of Gram-positive pathogenic bacteria as targets for antimicrobial therapy. Pharmacol. Ther. 93:293305.
86. Stephenson, K.,, Y. Yamaguchi,, and J. A. Hoch. 2000. The mechanism of action of inhibitors of bacterial twocomponent signal transduction systems. J. Biol. Chem. 275:3890038904.
87. Stevens, A. M.,, N. B. Shoemaker,, L. Y. Li,, and A. A. Salyers. 1993. Tetracycline regulation of genes on Bacteroides conjugative transposons. J. Bacteriol. 175:61346141.
88. Stock, A. M.,, J. M. Mottonen,, J. B. Stock,, and C. E. Schutt. 1989a. Three-dimensional structure of CheY, the response regulator of bacterial chemotaxis. Nature 337:745749.
89. Stock, A. M.,, V. L. Robinson,, and P. N. Goudreau. 2000. Two-component signal transduction. Annu. Rev. Biochem. 69:183215.
90. Stock, J. B.,, A. J. Ninfa,, and A. M. Stock. 1989b. Protein phosphorylation and regulation of adaptive responses in bacteria. Microbiol. Rev. 53:450490.
91. Strauch, M. A.,, D. deMendoza,, and J. A. Hoch. 1992. cis-Unsaturated fatty acids specifically inhibit a signaltransducing protein kinase required for initiation of sporulation in Bacillus subtilis. Mol. Microbiol. 6:29092917.
92. Sui, Z.,, J. Guan,, D. J. Hlasta,, M. J. Macielag,, B. D. Foleno,, R. M. Goldschmidt,, M. J. Loeloff,, G. C. Webb,, and J. F. Barret. 1998. SAR studies of diaryltriazoles against bacterial two-component regulatory systems and their antibacterial activities. Bioorg. Med. Chem. Lett. 8:19291934.
93. Swanson, R. V.,, R. B. Bourret,, and M. I. Simon. 1993. Intermolecular complementation of the kinase activity of CheA. Mol. Microbiol. 8:435441.
94. Szurmant, H.,, M. W. Bunn,, V. J. Cannistraro,, and G. W. Ordal. 2003. Bacillus subtilis hydrolyzes CheY-P at the location of its action, the flagellar switch. J. Biol. Chem. 278:4861148616.
95. Tanaka, T.,, S. K. Saha,, C. Tomomori,, R. Ishima,, D. Liu,, K. I. Tong,, H. Park,, R. Dutta,, L. Qin,, M. B. Swindells,, T. Yamazaki,, A. M. Ono,, M. Kainosho,, M. Inouye,, and M. Ikura. 1998. NMR structure of the histidine kinase domain of the E. coli osmosensor EnvZ. Nature 396:8892.
96. Throup, J. P.,, K. K. Koretke,, A. P. Bryant,, K. A. Ingraham,, A. F. Chalker,, Y. Ge,, A. Marra,, N. G. Wallis,, J. R. Brown,, D. J. Holmes,, M. Rosenberg,, and M. K. Burnham. 2000. A genomic analysis of two-component signal transduction in Streptococcus pneumoniae. Mol. Microbiol. 35:566576.
97. Tomomori, C.,, T. Tanaka,, R. Dutta,, H. Park,, S. K. Saha,, Y. Zhu,, R. Ishima,, D. Liu,, K. I. Tong,, H. Kurokawa,, H. Qian,, M. Inouye,, and M. Ikura. 1999. Solution structure of the homodimeric core domain of Escherichia coli histidine kinase EnvZ. Nat. Struct. Biol. 6:729734.
98. Trew, S. J.,, S. K. Wrigley,, L. Pairet,, J. Sohal,, P. Shanu-Wilson,, M. A. Hayes,, S. M. Martin,, R. N. Manohar,, M. I. Chicarelli-Robinson,, D. A. Kau,, C. V. Byrne,, E. M. Wellington,, J. M. Moloney,, J. Howard,, D. Hupe,, and E. R. Olson. 2000. Novel streptopyrroles from Streptomyces rimosus with bacterial protein histidine kinase inhibitory and antimicrobial activities. J. Antibiot. 53:111.
99. Varughese, K. I.,, Madhusudan, X. Z., Zhou, J. M., Whiteley,, and J. A. Hoch. 1998. Formation of a novel fourhelix bundle and molecular recognition sites by dimerization of a response regulator phosphotransferase. Mol. Cell 2:485493.
100. Volz, K.,, and P. Matsumura. 1991. Crystal structure of Escherichia coli CheY refined at 1.7 Å resolution. J. Biol. Chem. 266:1551115519.
101. Walsh, C. T.,, S. L. Fisher,, I. S. Park,, M. Prahalad,, and Z. Wu. 1996. Bacterial resistance to vancomycin: five genes and one missing hydrogen bond tell the story. Chem. Biol. 3:2128.
102. Weidner-Wells, M. A.,, K. A. Ohemeng,, V. N. Nguyen,, S. Fraga-Spano,, M. J. Macielag,, H. M. Werblood,, B. D. Foleno,, G. C. Webb,, J. F. Barret,, and D. J. Hlasta. 2001. Amidino benzimidazole inhibitors of bacterial two-component systems. Bioorg. Med. Chem. Lett. 11:15451548.
103. Welch, M.,, N. Chinardet,, L. Mourey,, C. Birck,, and J.-P. Samama. 1998. Structure of the CheY-binding domain of histidine kinase CheA in complex with CheY. Nat. Struct. Biol. 5:2529.
104. Welch, M.,, K. Oosawa,, S.-I. Aizawa,, and M. Eisenbach. 1994. Effects of phosphorylation, Mg2+, and conformation of the chemotaxis protein CheY on its binding to the flagellar switch protein FliM. Biochemistry 33:1047010476.
105. Welch, M.,, K. Oosawa,, S.-I. Aizawa,, and M. Eisenbach. 1993. Phosphorylation-dependent binding of a signal molecule to the flagellar switch of bacteria. Proc. Natl. Acad. Sci. USA 90:87878791.
106. Wolfe, A. J.,, and R. C. Stewart. 1993. The short form of the CheA protein restores kinase activity and chemotactic ability to kinase-deficient mutants. Proc. Natl. Acad. Sci. USA 90:15181522.
107. Wu, J.,, J. Li,, G. Li,, D. G. Long,, and R. M. Weis. 1996. The receptor binding site for the methyltransferase of bacterial chemotaxis is distinct from the sites of methylation. Biochemistry 35:49844993.
108. Wyman, C.,, I. Rombel,, A. K. North,, C. Bustamente,, and S. Kustu. 1997. Unusual oligomerization required for activity of NtrC, a bacterial enhancer-binding protein. Science 275:16581661.
109. Xu, Q.,, and A. H. West. 1999. Conservation of structure and function among histidine-containing phosphotransfer (HPt) domains as revealed by the crystal structure of YPD1. J. Mol. Biol. 292:10391050.
110. Yang, Y.,, and M. Inouye. 1991. Intermolecular complementation between two defective mutant signal transducing receptors. Proc. Natl. Acad. Sci. USA 88:1105711061.
111. Zahrt, T. C.,, and V. Deretic. 2000. An essential two-component signal transduction system in Mycobacterium tuberculosis. J. Bacteriol. 182:38323838.
112. Zhao, R.,, E. J. Collins,, R. B. Bourret,, and R. E. Silversmith. 2002. Structure and catalytic mechanism of the E. coli chemotaxis phosphatase CheZ. Nat. Struct. Biol. 9:570575.
113. Zhou, H.,, D. F. Lowry,, R. V. Swanson,, M. I. Simon,, and F. W. Dahlquist. 1995. NMR studies of the phosphotransfer domain of the histidine kinase CheA from Escherichia coli: assignments, secondary structure, general fold, and backbone dynamics. Biochemistry 34:1385813870.

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