title: Crystal structure of a complex of HIV-1 protease with a dihydroxyethylene-containing inhibitor: comparisons with molecular modeling.
abstract: The structure of a crystal complex of recombinant human immunodeficiency virus type 1 (HIV-1) protease with a peptide-mimetic inhibitor containing a dihydroxyethylene isostere insert replacing the scissile bond has been determined. The inhibitor is Noa-His-Hch psi [CH(OH)CH(OH)]Vam-Ile-Amp (U-75875), and its Ki for inhibition of the HIV-1 protease is < 1.0 nM (Noa = 1-naphthoxyacetyl, Hch = a hydroxy-modified form of cyclohexylalanine, Vam = a hydroxy-modified form of valine, Amp = 2-pyridylmethylamine). The structure of the complex has been refined to a crystallographic R factor of 0.169 at 2.0 A resolution by using restrained least-squares procedures. Root mean square deviations from ideality are 0.02 A and 2.4 degrees, for bond lengths and angles, respectively. The bound inhibitor diastereomer has the R configurations at both of the hydroxyl chiral carbon atoms. One of the diol hydroxyl groups is positioned such that it forms hydrogen bonds with both the active site aspartates, whereas the other interacts with only one of them. Comparison of this X-ray structure with a model-built structure of the inhibitor, published earlier, reveals similar positioning of the backbone atoms and of the side-chain atoms in the P2-P2' region, where the interaction with the protein is strongest. However, the X-ray structure and the model differ considerably in the location of the P3 and P3' end groups, and also in the positioning of the second of the two central hydroxyl groups. Reconstruction of the central portion of the model revealed the source of the hydroxyl discrepancy, which, when corrected, provided a P1-P1' geometry very close to that seen in the X-ray structure.
authors.affiliation: Macromolecular Structure Laboratory, NCI-Frederick Cancer Research and Development Center, ABL-Basic Research Program, Maryland 21702.
authors.forename: N
authors.initials: N
authors.lastname: Thanki
authors.forename: J K
authors.initials: JK
authors.lastname: Rao
authors.forename: S I
authors.initials: SI
authors.lastname: Foundling
authors.forename: W J
authors.initials: WJ
authors.lastname: Howe
authors.forename: J B
authors.initials: JB
authors.lastname: Moon
authors.forename: J O
authors.initials: JO
authors.lastname: Hui
authors.forename: A G
authors.initials: AG
authors.lastname: Tomasselli
authors.forename: R L
authors.initials: RL
authors.lastname: Heinrikson
authors.forename: S
authors.initials: S
authors.lastname: Thaisrivongs
authors.forename: A
authors.initials: A
authors.lastname: Wlodawer
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011994:Recombinant Proteins; C065978:U 75875; D016333:HIV Protease