The Hsp90 inhibitor radicicol interacts with the ATP-binding pocket of bacterial sensor kinase PhoQ.
Sensor kinases in the bacterial two-component system share a unique ATP-binding Bergerat fold with the GHL (gyrase, Hsp90, and MutL) family of proteins. We demonstrated that selected GHL inhibitors bind to the catalytic domain of sensor kinase PhoQ (PhoQcat) using NMR chemical shift perturbation experiments. Using crystallographic approaches, we show that radicicol (an Hsp90 inhibitor) binds and interacts specifically with residues in the ATP-binding pocket of PhoQ. The interaction between radicicol and PhoQcat demonstrates significant similarities as well as differences compared to AMPPNP (a non-hydrolyzable ATP analog) bound to PhoQcat and radicicol bound to Hsp90. Our results suggest that GHL inhibitors may be useful lead compounds for developing sensor kinase inhibitors.
Guarnieri
Michael T
MT
Department of Biochemistry and Molecular Genetics, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA.
Zhang
Lingdi
L
Shen
Jingping
J
Zhao
Rui
R
D000255:Adenosine Triphosphate / Q000737:chemistry; D000266:Adenylyl Imidodiphosphate / Q000737:chemistry; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D016227:Benzoquinones / Q000737:chemistry; D020134:Catalytic Domain; D003593:Cytoplasm / Q000201:enzymology; D027081:DNA Gyrase / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D047029:Lactams, Macrocyclic / Q000737:chemistry; D018942:Macrolides / Q000737:chemistry* / Q000494:pharmacology; D008969:Molecular Sequence Data; D009675:Novobiocin / Q000737:chemistry; D011487:Protein Conformation; D059005:Topoisomerase II Inhibitors
D001426:Bacterial Proteins; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018942:Macrolides; C079792:PhoQ protein, Bacteria; D059005:Topoisomerase II Inhibitors; D009675:Novobiocin; D000266:Adenylyl Imidodiphosphate; D000255:Adenosine Triphosphate; D027081:DNA Gyrase; C035359:monorden; C001277:geldanamycin