The Conformation of a Peptidyl Methyl Ketone Inhibitor Bound to the Human Cytomegalovirus Protease

Steven R LaPlante; Dale R Cameron; Norman Aubry; Pierre R Bonneau; Robert Déziel; Chantal Grand-Maître; William W Ogilvie; Stephen H Kawai

doi:10.1002/(SICI)1521-3773(19981016)37:19<2729::AID-ANIE2729>3.0.CO;2-4

The Conformation of a Peptidyl Methyl Ketone Inhibitor Bound to the Human Cytomegalovirus Protease

Angew Chem Int Ed Engl. 1998 Oct 16;37(19):2729-2732. doi: 10.1002/(SICI)1521-3773(19981016)37:19<2729::AID-ANIE2729>3.0.CO;2-4.

Authors

Steven R LaPlante¹, Dale R Cameron¹, Norman Aubry¹, Pierre R Bonneau¹, Robert Déziel¹, Chantal Grand-Maître¹, William W Ogilvie¹, Stephen H Kawai¹

Affiliation

¹ Departments of Chemistry and Biological Sciences, Bio-Méga Research Division, Boehringer Ingelheim (Canada) Ltd., 2100 Cunard St., Laval, Québec, H7S 2G5 (Canada), Fax: (+1) 514-682-8434.

Abstract

A weak inhibitor means faster exchange! Since the methyl ketone MK2 is a weak noncovalent peptidyl inhibitor of the human cytomegalovirus protease, exchange between the free and enzyme-bound forms is rapid. This allows for the use of transferred NOE NMR methods and molecular modeling, which show that the bound conformation of MK2 is an extended peptide. This is confirmed by the results of an X-ray crystallographic analysis of a related enzyme-inhibitor complex.

Keywords: Conformation analysis; Molecular modeling; NMR spectroscopy; Peptidomimetics.