Abstract
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 Mg(2+) or Mn(2+). 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 gamma-phosphate and its associated Mg(2+) 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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenosine Diphosphate / metabolism*
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Adenosine Triphosphatases / antagonists & inhibitors
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Adenosine Triphosphatases / chemistry
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Adenosine Triphosphatases / metabolism
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Adenosine Triphosphate / analogs & derivatives
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Adenosine Triphosphate / metabolism*
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Bacterial Proteins*
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Binding Sites
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Cations, Divalent / metabolism
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Chromatography, Gel
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Crystallography, X-Ray
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Histidine Kinase
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Hydrogen Bonding
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Magnesium / metabolism
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / chemistry*
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Membrane Proteins / metabolism*
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Methyl-Accepting Chemotaxis Proteins
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Models, Molecular
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Phosphorylation
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Protein Kinase Inhibitors
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Protein Kinases / chemistry*
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Protein Kinases / metabolism*
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Protein Structure, Tertiary
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Solvents
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Thermotoga maritima / enzymology*
Substances
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Bacterial Proteins
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Cations, Divalent
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Membrane Proteins
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Methyl-Accepting Chemotaxis Proteins
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Protein Kinase Inhibitors
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Solvents
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Adenosine Diphosphate
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Adenosine Triphosphate
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Protein Kinases
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Histidine Kinase
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Adenosine Triphosphatases
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Magnesium
Associated data
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PDB/1I58
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PDB/1I59
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PDB/1I5A
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PDB/1I5B
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PDB/1I5C
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PDB/1I5D