title: Three-dimensional solution structure of the HIV-1 protease complexed with DMP323, a novel cyclic urea-type inhibitor, determined by nuclear magnetic resonance spectroscopy.
abstract: The three-dimensional solution structure of the HIV-1 protease homodimer, MW 22.2 kDa, complexed to a potent, cyclic urea-based inhibitor, DMP323, is reported. This is the first solution structure of an HIV protease/inhibitor complex that has been elucidated. Multidimensional heteronuclear NMR spectra were used to assemble more than 4,200 distance and angle constraints. Using the constraints, together with a hybrid distance geometry/simulated annealing protocol, an ensemble of 28 NMR structures was calculated having no distance or angle violations greater than 0.3 A or 5 degrees, respectively. Neglecting residues in disordered loops, the RMS deviation (RMSD) for backbone atoms in the family of structures was 0.60 A relative to the average structure. The individual NMR structures had excellent covalent geometry and stereochemistry, as did the restrained minimized average structure. The latter structure is similar to the 1.8-A X-ray structure of the protease/DMP323 complex (Chang CH et al., 1995, Protein Science, submitted); the pairwise backbone RMSD calculated for the two structures is 1.22 A. As expected, the mismatch between the structures is greatest in the loops that are disordered and/or flexible. The flexibility of residues 37-42 and 50-51 may be important in facilitating substrate binding and product release, because these residues make up the respective hinges and tips of the protease flaps. Flexibility of residues 4-8 may play a role in protease regulation by facilitating autolysis.
authors.affiliation: Molecular Structural Biology Unit, NIDR, Bethesda, Maryland 20892, USA.
authors.forename: T
authors.initials: T
authors.lastname: Yamazaki
authors.forename: A P
authors.initials: AP
authors.lastname: Hinck
authors.forename: Y X
authors.initials: YX
authors.lastname: Wang
authors.forename: L K
authors.initials: LK
authors.lastname: Nicholson
authors.forename: D A
authors.initials: DA
authors.lastname: Torchia
authors.forename: P
authors.initials: P
authors.lastname: Wingfield
authors.forename: S J
authors.initials: SJ
authors.lastname: Stahl
authors.forename: J D
authors.initials: JD
authors.lastname: Kaufman
authors.forename: C H
authors.initials: CH
authors.lastname: Chang
authors.forename: P J
authors.initials: PJ
authors.lastname: Domaille
authors.forename: P Y
authors.initials: PY
authors.lastname: Lam
mesh_terms: D001381:Azepines; D004926:Escherichia coli / Q000235:genetics; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011522:Protons; D011994:Recombinant Proteins / Q000235:genetics; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014764:Viral Proteins / Q000737:chemistry
chemical_list: D001381:Azepines; D017320:HIV Protease Inhibitors; D011522:Protons; D011994:Recombinant Proteins; D014764:Viral Proteins; D014508:Urea; D016333:HIV Protease; C085816:DMP 323