The structure of the KinA-Sda complex suggests an allosteric mechanism of histidine kinase inhibition.
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.
Whitten
Andrew E
AE
Bragg Institute, Australian Nuclear Science and Technology Organisation, Lucas Heights 2234, Australia.
Jacques
David A
DA
Hammouda
Boualem
B
Hanley
Tracey
T
King
Glenn F
GF
Guss
J Mitchell
JM
Trewhella
Jill
J
Langley
David B
DB
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
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