title: The structure of the KinA-Sda complex suggests an allosteric mechanism of histidine kinase inhibition.
abstract: The Bacillus subtilis histidine kinase KinA controls activation of the transcription factor governing sporulation, Spo0A. The decision to sporulate involves KinA phosphorylating itself on a conserved histidine residue, after which the phosphate moiety is relayed via two other proteins to Spo0A. The DNA-damage checkpoint inhibitor Sda halts this pathway by binding KinA and blocking the autokinase reaction. We have performed small-angle X-ray scattering and neutron contrast variation studies on the complex formed by KinA and Sda. The data show that two Sda molecules bind to the base of the DHp dimerization domain of the KinA dimer. In this position Sda does not appear to be able to sterically block the catalytic domain from accessing its target histidine, as previously proposed, but rather may effect an allosteric mode of inhibition involving transmission of the inhibitory signal via the four-helix bundle that forms the DHp domain.
authors.affiliation: Bragg Institute, Australian Nuclear Science and Technology Organisation, Lucas Heights 2234, Australia.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Whitten
authors.forename: David A
authors.initials: DA
authors.lastname: Jacques
authors.forename: Boualem
authors.initials: B
authors.lastname: Hammouda
authors.forename: Tracey
authors.initials: T
authors.lastname: Hanley
authors.forename: Glenn F
authors.initials: GF
authors.lastname: King
authors.forename: J Mitchell
authors.initials: JM
authors.lastname: Guss
authors.forename: Jill
authors.initials: J
authors.lastname: Trewhella
authors.forename: David B
authors.initials: DB
authors.lastname: Langley
mesh_terms: D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D001412:Bacillus subtilis / Q000201:enzymology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D019281:Dimerization; D000071677:Histidine Kinase; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009502:Neutrons; D011485:Protein Binding; D011494:Protein Kinases / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012542:Scattering, Radiation; D012996:Solutions; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D012996:Solutions; C075521:kinA protein, Bacillus subtilis; C422745:suppressor of DnaA, Bacillus subtilis; D011494:Protein Kinases; D000071677:Histidine Kinase