TAILIEUCHUNG - Báo cáo khoa học: Role of hydroxyl group and R/S configuration of isostere in binding properties of HIV-1 protease inhibitors

The crystal structure of the complex between human immunodeficiency virus type 1 (HIV-1) protease and a peptidomimetic inhibitor of ethyleneamine type has been refined toRfactor of with diffraction limit A ˚ .The peptidomimetic inhibitor Boc-Phe-Y[CH2CH2 NH]-Phe-Glu-Phe-NH2 (denoted here as OE) contains the ethylene-amine replacement of the scissilepeptidebond. The inhibitor lacks the hydroxyl group which is believed to mimic tetra-hedral transition state of proteolytic reaction and thus is suspected to be necessary for good properties of peptido-mimetic HIV-1 protease inhibitors | Eur. J. Biochem. 271 4451-4461 2004 FEBS 2004 doi Role of hydroxyl group and RS configuration of isostere in binding properties of HIV-1 protease inhibitors Hana Petrokova1 Jarmila Duskova1. Jan Dohnalek1 Tereza Skálová1 Eva Vondrácková-Buchtelová1 Milan Soucek2 Jan Konvalinka2 Jiri Brynda3 Milan Fabry3 Juraj Sedlacek3 and Jindrich Hasek1 1 Institute of Macromolecular Chemistry 2Institute of Organic Chemistry and Biochemistry and 3Institute of Molecular Genetics Academy of Sciences of the Czech Republic Praha Czech Republic The crystal structure of the complex between human immunodeficiency virus type 1 HIV-1 protease and a peptidomimetic inhibitor of ethyleneamine type has been refined to R factor of with diffraction limit A. The peptidomimetic inhibitor Boc-Phe-Y CH2CH2NH -Phe-Glu-Phe-NH2 denoted here as OE contains the ethyleneamine replacement of the scissile peptide bond. The inhibitor lacks the hydroxyl group which is believed to mimic tetrahedral transition state of proteolytic reaction and thus is suspected to be necessary for good properties of peptido-mimetic HIV-1 protease inhibitors. Despite the missing hydroxyl group the inhibition constant of OE is nM and it remains in the nanomolar range also towards several available mutants of HIV-1 protease. The inhibitor was found in the active site of protease in an extended conformation with a unique hydrogen bond pattern different from hydroxyethylene and hydroxyethylamine inhibitors. The isostere nitrogen forms a hydrogen bond to one catalytic aspartate only. The other aspartate forms two weak hydrogen bridges to the ethylene group of the isostere. A comparison with other inhibitors of this series containing isostere hydroxyl group in R or S configuration shows different ways of accommodation of inhibitor in the active site. Special attention is devoted to intermolecular contacts between neighbouring dimers responsible for mutual protein adhesion and for a .

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