Download MendeleyInteractions of a new alpha-aminophosphinic derivative inside the active site of TLN (thermolysin): a model for zinc-metalloendopeptidase inhibition.
Selkti, M., Tomas, A., Gaucher, J.F., Prange, T., Fournie-Zaluski, M.C., Chen, H., Roques, B.P.(2003) Acta Crystallogr D Biol Crystallogr 59: 1200-1205
- PubMed: 12832763
- DOI: https://doi.org/10.1107/s0907444903010060
- Primary Citation of Related Structures:
1OS0 - PubMed Abstract:
A new alpha-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 alpha-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 alpha-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.
Organizational Affiliation:
Laboratoire de Cristallographie et RMN Biologiques (UMR 8015 CNRS), 4 Avenue de l'Observatoire, 75270 Paris CEDEX 06, France. selkti@pharmacie.univ-paris5.fr
