title: Structural and biochemical characterization of the inhibitor complexes of xenotropic murine leukemia virus-related virus protease.
abstract: Interactions between the protease (PR) encoded by the xenotropic murine leukemia virus-related virus and a number of potential inhibitors have been investigated by biochemical and structural techniques. It was observed that several inhibitors used clinically against HIV PR exhibit nanomolar or even subnanomolar values of K(i) , depending on the exact experimental conditions. Both TL-3, a universal inhibitor of retroviral PRs, and some inhibitors originally shown to inhibit plasmepsins were also quite potent, whereas inhibition by pepstatin A was considerably weaker. Crystal structures of the complexes of xenotropic murine leukemia virus-related virus PR with TL-3, amprenavir and pepstatin A were solved at high resolution and compared with the structures of complexes of these inhibitors with other retropepsins. Whereas TL-3 and amprenavir bound in a predictable manner, spanning the substrate-binding site of the enzyme, two molecules of pepstatin A bound simultaneously in an unprecedented manner, leaving the catalytic water molecule in place.
authors.affiliation: Protein Structure Section, Macromolecular Crystallography Laboratory, National Cancer Institute, Frederick, MD 21702-1201, USA.
authors.forename: Mi
authors.initials: M
authors.lastname: Li
authors.forename: Alla
authors.initials: A
authors.lastname: Gustchina
authors.forename: Krisztina
authors.initials: K
authors.lastname: Matúz
authors.forename: Jozsef
authors.initials: J
authors.lastname: Tözsér
authors.forename: Sirilak
authors.initials: S
authors.lastname: Namwong
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Goldfarb
authors.forename: Ben M
authors.initials: BM
authors.lastname: Dunn
authors.forename: Alexander
authors.initials: A
authors.lastname: Wlodawer
mesh_terms: D000818:Animals; D001665:Binding Sites; D002219:Carbamates / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D019281:Dimerization; D005663:Furans; D051379:Mice; D008958:Models, Molecular; D010436:Pepstatins / Q000494:pharmacology*; D010447:Peptide Hydrolases / Q000737:chemistry* / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D013449:Sulfonamides / Q000494:pharmacology*; D058008:Xenotropic murine leukemia virus-related virus / Q000201:enzymology*
chemical_list: D002219:Carbamates; D005663:Furans; D010436:Pepstatins; D011480:Protease Inhibitors; D013449:Sulfonamides; C095108:amprenavir; D010447:Peptide Hydrolases; C031375:pepstatin