title: Hydroxyethylamine isostere of an HIV-1 protease inhibitor prefers its amine to the hydroxy group in binding to catalytic aspartates. A synchrotron study of HIV-1 protease in complex with a peptidomimetic inhibitor.
abstract: A complex structure of HIV-1 protease with a hydroxyethylamine-containing inhibitor Boc-Phe-Psi[(S)-CH(OH)CH2NH]-Phe-Gln-Phe-NH2 has been determined by X-ray diffraction to 1.8 A resolution. The inhibitor is bound in the active site of the protease dimer with its hydroxyethylamine isostere participating in hydrogen bonds to the catalytic aspartates 25 and 25' and glycine 27' of the active site triads via five hydrogen bonds. The isostere amine interactions with the catalytic aspartates result in a displacement of the isostere hydroxy group in comparison with the common position known for analogous hydroxyethylamine containing inhibitors. A comparison with another inhibitor of this series shows that the change of one atom of the P2' side chain (Glu/Gln) leads to an altered ability of creating hydrogen bonds to the active site and within the inhibitor molecule. The diffraction data collected at a synchrotron radiation source enabled a detailed analysis of the complex solvation and of alternative conformations of protein side chains.
authors.affiliation: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Praha 6, Czech Republic. dohnalek@imc.cas.cz
authors.forename: Jan
authors.initials: J
authors.lastname: Dohnálek
authors.forename: Jindrich
authors.initials: J
authors.lastname: Hasek
authors.forename: Jarmila
authors.initials: J
authors.lastname: Dusková
authors.forename: Hana
authors.initials: H
authors.lastname: Petroková
authors.forename: Martin
authors.initials: M
authors.lastname: Hradilek
authors.forename: Milan
authors.initials: M
authors.lastname: Soucek
authors.forename: Jan
authors.initials: J
authors.lastname: Konvalinka
authors.forename: Jirí
authors.initials: J
authors.lastname: Brynda
authors.forename: Juraj
authors.initials: J
authors.lastname: Sedlácek
authors.forename: Milan
authors.initials: M
authors.lastname: Fábry
mesh_terms: D000588:Amines / Q000737:chemistry*; D000596:Amino Acids / Q000737:chemistry; D001224:Aspartic Acid / Q000737:chemistry*; D001665:Binding Sites; D002384:Catalysis; D019281:Dimerization; D010450:Endopeptidases / Q000737:chemistry; D004983:Ethanolamines / Q000737:chemistry*; D005990:Glycerol / Q000737:chemistry; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D006860:Hydrogen Bonding; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D010100:Oxygen / Q000737:chemistry; D010446:Peptide Fragments; D011485:Protein Binding; D011487:Protein Conformation; D017356:Synchrotrons; D014961:X-Ray Diffraction
chemical_list: D000588:Amines; D000596:Amino Acids; D004983:Ethanolamines; D017320:HIV Protease Inhibitors; D010446:Peptide Fragments; D001224:Aspartic Acid; D010450:Endopeptidases; D016333:HIV Protease; D005990:Glycerol; D010100:Oxygen