Nonantibiotic properties of tetracyclines: structural basis for inhibition of secretory phospholipase A2. - École polytechnique Accéder directement au contenu
Article Dans Une Revue Journal of Molecular Biology Année : 2010

Nonantibiotic properties of tetracyclines: structural basis for inhibition of secretory phospholipase A2.

Résumé

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.

Dates et versions

hal-00488178 , version 1 (01-06-2010)

Identifiants

Citer

Daniela Dalm, Gottfried J. Palm, Alexey Aleksandrov, Thomas Simonson, Winfried Hinrichs. Nonantibiotic properties of tetracyclines: structural basis for inhibition of secretory phospholipase A2.. Journal of Molecular Biology, 2010, 398 (1), pp.83-96. ⟨10.1016/j.jmb.2010.02.049⟩. ⟨hal-00488178⟩
332 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More