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Biological Crystallography Interactions of a new a-aminophosphinic derivative inside the active site of TLN (thermolysin): a model for zinc-metalloendopeptidase inhibition

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Selkti, Mohamed | Tomas, Alain | Gaucher, Jean-François | Prangé, Thierry | Fournié-Zaluski, Marie-Claude | Chen, Huixiong | Roques, Bernard-Pierre

Edité par CCSD ; International Union of Crystallography -

International audience. A new-aminophosphinic compound able to inhibit both zinc-containing exopeptidases and endopeptidases has been crystallized with TLN as a model in order to investigate the mode of zinc recognition by the phosphinic moiety and to evaluate the potential role of the free-amino group in the formation of enzyme±inhibitor complexes. In addition to the main interactions between the backbone of the inhibitor and the enzyme active site, it is observed that the phosphinic group acts as a distorted bidentate ligand for the zinc ion, while the free-amino function does not directly participate in interactions within the active site. Association of the present data and the K i values of various analogues of the inhibitor towards TLN and neprilysin suggests differences in the hydrophobicity of the S 1 ±S 2 domains of the enzymes. This could be taken into account in the design of selective inhibitors.

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