title: Interactions of a new alpha-aminophosphinic derivative inside the active site of TLN (thermolysin): a model for zinc-metalloendopeptidase inhibition.
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.
authors.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
authors.forename: Mohamed
authors.initials: M
authors.lastname: Selkti
authors.forename: Alain
authors.initials: A
authors.lastname: Tomas
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gaucher
authors.forename: Thierry
authors.initials: T
authors.lastname: Prangé
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Fournié-Zaluski
authors.forename: Huixiong
authors.initials: H
authors.lastname: Chen
authors.forename: Bernard-Pierre
authors.initials: BP
authors.lastname: Roques
mesh_terms: D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D009943:Organophosphorus Compounds / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013820:Thermolysin / Q000737:chemistry*; D015032:Zinc
chemical_list: D004791:Enzyme Inhibitors; D009943:Organophosphorus Compounds; D008666:Metalloendopeptidases; D013820:Thermolysin; D015032:Zinc