Abstract

Anisotropic Dynamics of the JE-2147-HIV Protease complex: Drug Resistance and Thermodynamic Binding Mode Examined in a 1.09Å Structure.

Reiling, K., Endres, N., Dauber, D., Craik, C., Stroud, R.

Biochemistry 41 No 14 4582 –4594. (2002)
PDB accession No. 1KZK
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The structure of JE-2147 bound to HIV protease (Pr) was determined to 1.09A resolution, the highest resolution to date for HIV Pr, which allows the characterization of atomic motion by anisotropic displacement parameters (ADPs). A clustering analysis, based on the directional information inherent to ADP tensors, defines two sets of sub-domains of the protein that undergo similar anisotropic motion. These sets group together as a) the core of monomer A grouped with both substrate binding flaps, and b) the core of monomer B coupled to both catalytic aspartates (25A/B). The _-sheet, residues 1-4 and 95-99, that form part of the dimer interface between monomers, each exhibit large anisotropic amplitudes that differ from those of the other monomer, or the other sets of domains. The JE2147 complex is used to assess structure activity relationships for this second-generation, HIV Pr inhibitor whose binding is enthalpically driven, in contrast to first-generation inhibitors, that are predominantly entropy driven. Comparison with other entropy driven HIV-Pr drug-complexes indicates a ~0.5 ß movement of the substrate flaps of the protease toward the substrate-binding cleft in the JE-2147 complex. Rigid-body domains of the protease identified by ADP profile clustering and the mobility of the dimer interface suggest a model of entropy-enthalpy compensation for HIV protease inhibitors. High affinity, enthalpic inhibitors such as JE-2147 (41 ± 18 pM) effectively coalesce the binding flaps of the enzyme into a rigid unit. Transition of the dimer interface toward the less ordered state upon inhibitor binding provides entropic compensation for flap fixation.

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