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Published April 2001 | public
Journal Article

Nucleotide binding by the histidine kinase CheA


To probe the structural basis for protein histidine kinase (PHK) catalytic activity and the prospects for PHK-specific inhibitor design, we report the crystal structures for the nucleotide binding domain of Thermotoga maritima CheA with ADP and three ATP analogs (ADPNP, ADPCP and TNP-ATP) bound with either Mg2+ or Mn2+. The conformation of ADPNP bound to CheA and related ATPases differs from that reported in the ADPNP complex of PHK EnvZ. Interactions of the active site with the nucleotide bold gamma-phosphate and its associated Mg2+ ion are linked to conformational changes in an ATP-lid that could mediate recognition of the substrate domain. The inhibitor TNP-ATP binds CheA with its phosphates in a nonproductive conformation and its adenine and trinitrophenyl groups in two adjacent binding pockets. The trinitrophenyl interaction may be exploited for designing CheA-targeted drugs that would not interfere with host ATPases.

Additional Information

© 2001 Nature Publishing Group. Received 17 November, 2000; accepted 31 January, 2001. The authors wish to thank: D.C Rees; P.J. Bjorkman; the Stanford Synchrotron Radiation Laboratory (Palo Alto) for access to X-ray diffraction facilities and T. Iverson for assistance; D.B. Wigley for providing the coordinates of GyrB complexed with ADPNP; L.A. Alex and Y.-H. Hu for assistance in the early stages of the project; T.-M. Yi for helpful discussions and critical reading of the manuscript; and D.C. Rees, T.O. Yeates, and J. Greenwald for advice on crystal twinning. This work is supported by the NIH, a Donald E. and Delia B. Baxter Foundation Fellowship to A.M.B. and a NIH predoctoral fellowship to C.M.Q. Coordinates have been deposited in the Protein Data Bank. The accession codes are as follows: ADPCP-Mg 1I58; ADPNP-Mg 1I59; ADPCP-Mn 1I5A; ADPNP-Mn 1I5B; ADP-1I5C; TNP-ATP 1I5D.

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