title: Solution structure of the HIV protease inhibitor acetyl-pepstatin as determined by NMR and molecular modeling.
abstract: The structure of acetyl-pepstatin has been investigated in solution by two-dimensional NMR spectroscopy and molecular modeling. The analysis of DQFCOSY, TOCSY and NOESY spectra lead to a full assignment of the -NMR signals both in DMSO-d6 and in TFE-d3:H2O 1:1. Interproton distances, dihedral angles and exchanger regimes of NH or OH protons were derived from ROESY connectivities, coupling constants and temperature dependences of the chemical shifts, respectively. Molecular modeling using the NMR distance and dihedral angle constraints obtained in DMSO-d6 yielded a model showing a well-defined structure for the N-terminal segment Ac-1 to Sta-4, but a flexible structure for the C-terminal segment. The structure was less defined in TFE-d3:H2O 1:1 and 13C T1 measurements are indicative of higher mobility. Comparison of the NMR-determined solution structure of acetyl-pepstatin with its crystal structure when bound to HIV-1 protease shows that the conformation is more extended in the complex as a result of intermolecular interactions.
authors.affiliation: INRS-Santé, Université du Québec, Pointe-Claire, Québec, Canada. Yvan_Boulanger@INRS-Sante.UQuebec, CA
authors.forename: Y
authors.initials: Y
authors.lastname: van Boulanger
authors.forename: L
authors.initials: L
authors.lastname: Senécal
authors.forename: G
authors.initials: G
authors.lastname: Sauvé
mesh_terms: D002247:Carbon Isotopes; D016333:HIV Protease; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010436:Pepstatins / Q000737:chemistry*; D011487:Protein Conformation; D012996:Solutions; D013696:Temperature; D013997:Time Factors
chemical_list: D002247:Carbon Isotopes; D017320:HIV Protease Inhibitors; D010436:Pepstatins; D012996:Solutions; C014195:Streptomyces pepsin inhibitor; D016333:HIV Protease