title: X-ray crystal structures of human immunodeficiency virus type 1 protease mutants complexed with atazanavir.
abstract: Atazanavir, which is marketed as REYATAZ, is the first human immunodeficiency virus type 1 (HIV-1) protease inhibitor approved for once-daily administration. As previously reported, atazanavir offers improved inhibitory profiles against several common variants of HIV-1 protease over those of the other peptidomimetic inhibitors currently on the market. This work describes the X-ray crystal structures of complexes of atazanavir with two HIV-1 protease variants, namely, (i) an enzyme optimized for resistance to autolysis and oxidation, referred to as the cleavage-resistant mutant (CRM); and (ii) the M46I/V82F/I84V/L90M mutant of the CRM enzyme, which is resistant to all approved HIV-1 protease inhibitors, referred to as the inhibitor-resistant mutant. In these two complexes, atazanavir adopts distinct bound conformations in response to the V82F substitution, which may explain why this substitution, at least in isolation, has yet to be selected in vitro or in the clinic. Because of its nearly symmetrical chemical structure, atazanavir is able to make several analogous contacts with each monomer of the biological dimer.
authors.affiliation: Macromolecular Crystallography, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. herbert.klei@bms.com
authors.forename: Herbert E
authors.initials: HE
authors.lastname: Klei
authors.forename: Kevin
authors.initials: K
authors.lastname: Kish
authors.forename: Pin-Fang M
authors.initials: PF
authors.lastname: Lin
authors.forename: Qi
authors.initials: Q
authors.lastname: Guo
authors.forename: Jacques
authors.initials: J
authors.lastname: Friborg
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Rose
authors.forename: Yaqun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Valentina
authors.initials: V
authors.lastname: Goldfarb
authors.forename: David R
authors.initials: DR
authors.lastname: Langley
authors.forename: Michael
authors.initials: M
authors.lastname: Wittekind
authors.forename: Steven
authors.initials: S
authors.lastname: Sheriff
mesh_terms: D000069446:Atazanavir Sulfate; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral / Q000235:genetics; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism*
chemical_list: D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D016333:HIV Protease