How to switch off a histidine kinase: crystal structure of Geobacillus stearothermophilus KinB with the inhibitor Sda.
Entry to sporulation in bacilli is governed by a histidine kinase phosphorelay, a variation of the predominant signal transduction mechanism in prokaryotes. Sda directly inhibits sporulation histidine kinases in response to DNA damage and replication defects. We determined a 2.0-A-resolution X-ray crystal structure of the intact cytoplasmic catalytic core [comprising the dimerization and histidine phosphotransfer domain (DHp domain), connected to the ATP binding catalytic domain] of the Geobacillus stearothermophilus sporulation kinase KinB complexed with Sda. Structural and biochemical analyses reveal that Sda binds to the base of the DHp domain and prevents molecular transactions with the DHp domain to which it is bound by acting as a simple molecular barricade. Sda acts to sterically block communication between the catalytic domain and the DHp domain, which is required for autophosphorylation, as well as to sterically block communication between the response regulator Spo0F and the DHp domain, which is required for phosphotransfer and phosphatase activities.
Bick
Matthew J
MJ
The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Lamour
Valerie
V
Rajashankar
Kanagalaghatta R
KR
Gordiyenko
Yuliya
Y
Robinson
Carol V
CV
Darst
Seth A
SA
D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D001411:Geobacillus stearothermophilus / Q000201:enzymology* / Q000378:metabolism; D000071677:Histidine Kinase; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D013171:Spores, Bacterial / Q000378:metabolism
D001426:Bacterial Proteins; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D000071677:Histidine Kinase