title: Crystal structure of lysine sulfonamide inhibitor reveals the displacement of the conserved flap water molecule in human immunodeficiency virus type 1 protease.
abstract: Human immunodeficiency virus type 1 (HIV-1) protease has been continuously evolving and developing resistance to all of the protease inhibitors. This requires the development of new inhibitors that bind to the protease in a novel fashion. Most of the inhibitors that are on the market are peptidomimetics, where a conserved water molecule mediates hydrogen bonding interactions between the inhibitors and the flaps of the protease. Recently a new class of inhibitors, lysine sulfonamides, was developed to combat the resistant variants of HIV protease. Here we report the crystal structure of a lysine sulfonamide. This inhibitor binds to the active site of HIV-1 protease in a novel manner, displacing the conserved water and making extensive hydrogen bonds with every region of the active site.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
authors.forename: Madhavi N L
authors.initials: MN
authors.lastname: Nalam
authors.forename: Anik
authors.initials: A
authors.lastname: Peeters
authors.forename: Tim H M
authors.initials: TH
authors.lastname: Jonckers
authors.forename: Inge
authors.initials: I
authors.lastname: Dierynck
authors.forename: Celia A
authors.initials: CA
authors.lastname: Schiffer
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism
chemical_list: D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D016333:HIV Protease