title: Nonantibiotic properties of tetracyclines: structural basis for inhibition of secretory phospholipase A2.
abstract: Secretory phospholipase A(2) is involved in inflammatory processes and was previously shown to be inhibited by lipophilic tetracyclines such as minocycline (minoTc) and doxycycline. Lipophilic tetracyclines might be a new lead compound for the design of specific inhibitors of secretory phospholipase A(2), which play a crucial role in inflammatory processes. Our X-ray crystal structure analysis at 1.65 A resolution of the minoTc complex of phospholipase A(2) (PLA(2)) of the Indian cobra (Naja naja naja) is the first example of nonantibiotic tetracycline interactions with a protein. MinoTc interferes with the conformation of the active-site Ca(2+)-binding loop, preventing Ca(2)(+) binding, and shields the active site from substrate entrance, resulting in inhibition of the enzyme. MinoTc binding to PLA(2) is dominated by hydrophobic interactions quite different from antibiotic recognition of tetracyclines by proteins or the ribosome. The affinity of minoTc for PLA(2) was determined by surface plasmon resonance, resulting in a dissociation constant K(d)=1.8 x 10(-)(4) M.
authors.affiliation: Institute for Biochemistry, Department of Molecular Structural Biology, University of Greifswald, Felix-Hausdorff-Str. 4, D-17489 Greifswald, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Dalm
authors.forename: Gottfried J
authors.initials: GJ
authors.lastname: Palm
authors.forename: Alexey
authors.initials: A
authors.lastname: Aleksandrov
authors.forename: Thomas
authors.initials: T
authors.lastname: Simonson
authors.forename: Winfried
authors.initials: W
authors.lastname: Hinrichs
mesh_terms: D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004546:Elapid Venoms / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000201:enzymology; D017815:Elapidae; D007700:Kinetics; D008958:Models, Molecular; D054497:Phospholipases A2, Secretory / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D020349:Surface Plasmon Resonance; D013754:Tetracyclines / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004546:Elapid Venoms; D013754:Tetracyclines; D054497:Phospholipases A2, Secretory