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J. Biol. Chem., Vol. 269, Issue 42, 26344-26348, Oct, 1994
Z Chen, Y Li, E Chen, DL Hall, PL Darke, C Culberson, JA Shafer and LC Kuo
L-735,524 is a potent, orally bioavailable inhibitor of human
immunodeficiency virus (HIV) protease currently in a Phase II clinical
trial. We report here the three-dimensional structure of L-735,524
complexed to HIV-2 protease at 1.9-A resolution, as well as the structure
of the native HIV-2 protease at 2.5-A resolution. The structure of HIV-2
protease is found to be essentially identical to that of HIV-1 protease. In
the crystal lattice of the HIV-2 protease complexed with L-735,524, the
inhibitor is chelated to the active site of the homodimeric enzyme in one
orientation. This feature allows an unambiguous assignment of
protein-ligand interactions from the electron density map. Both Fourier and
difference Fourier maps reveal clearly the closure of the flap domains of
the protease upon L-735,524 binding. Specific interactions between the
enzyme and the inhibitor include the hydroxy group of the
hydroxyaminopentane amide moiety of L-735,524 ligating to the carboxyl
groups of the essential Asp-25 and Asp-25' enzymic residues and the amide
oxygens of the inhibitor hydrogen bonding to the backbone amide nitrogen of
Ile-50 and Ile-50' via an intervening water molecule. A second bridging
water molecule is found between the amide nitrogen N2 of L-735,524 and the
carboxyl oxygen of Asp-29'. Although other hydrogen bonds also add to
binding, an equally significant contribution to affinity arises from
hydrophobic interactions between the protease and the inhibitor throughout
the pseudo-symmetric S1/S1', S2/S2', and S3/S3' regions of the enzyme.
Except for its pyridine ring, all lipophilic moieties (t-butyl, indanyl,
benzyl, and piperidyl) of L-735,524 are rigidly defined in the active site.
Crystal structure at 1.9-A resolution of human immunodeficiency virus (HIV) II protease complexed with L-735,524, an orally bioavailable inhibitor of the HIV proteases
Department of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486.
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