Enzyme Inhibition by Allosteric Capture of an Inactive Conformation

Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158-2280, USA.
Journal of Molecular Biology (Impact Factor: 4.33). 06/2011; 411(5):999-1016. DOI: 10.1016/j.jmb.2011.06.032
Source: PubMed


All members of the human herpesvirus protease (HHV Pr) family are active as weakly associating dimers but inactive as monomers. A small-molecule allosteric inhibitor of Kaposi's sarcoma-associated herpesvirus protease (KSHV Pr) traps the enzyme in an inactive monomeric state where the C-terminal helices are unfolded and the hydrophobic dimer interface is exposed. NMR titration studies demonstrate that the inhibitor binds to KSHV Pr monomers with low micromolar affinity. A 2.0-Å-resolution X-ray crystal structure of a C-terminal truncated KSHV Pr-inhibitor complex locates the binding pocket at the dimer interface and displays significant conformational perturbations at the active site, 15 Å from the allosteric site. NMR and CD data suggest that the small molecule inhibits human cytomegalovirus protease via a similar mechanism. As all HHV Prs are functionally and structurally homologous, the inhibitor represents a class of compounds that may be developed into broad-spectrum therapeutics that allosterically regulate enzymatic activity by disrupting protein-protein interactions.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Granular bed filter (GBF) technology can be applied for high-temperature gas cleanup in integrated gasification combined-cycle (IGCC) and pressurized fluidized-bed combustion (PFBC) advanced coal-fired power plants. The design of the gas inlet component of the granular bed filter is important to achieve a uniform gas distribution and higher usage rate of the filter media. Previous studies show that the gas velocity at the inlet is not uniformly distributed. This non-uniformity may lead to a lower usage rate of the filter media. In this study a baffle device is introduced to the inlet system in order to achieve a more uniform gas velocity distribution. A more uniform gas inlet distribution can be obtained by adjustment of the lengths and angles of the baffles. The gas velocities along the inlet and filtration surfaces are measured using a pitot tube. The uniformity of the gas velocity distribution can be characterized by looking at the distributions of the standard deviation of the gas velocity and the differences in the mean velocities between the two filtration surfaces.
    No preview · Article · Nov 2010 · Advanced Powder Technology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Allosteric drugs are increasingly used because they produce fewer side effects. Allosteric signal propagation does not stop at the 'end' of a protein, but may be dynamically transmitted across the cell. We propose here that the concept of allosteric drugs can be broadened to 'allo-network drugs' - whose effects can propagate either within a protein, or across several proteins, to enhance or inhibit specific interactions along a pathway. We posit that current allosteric drugs are a special case of allo-network drugs, and suggest that allo-network drugs can achieve specific, limited changes at the systems level, and in this way can achieve fewer side effects and lower toxicity. Finally, we propose steps and methods to identify allo-network drug targets and sites that outline a new paradigm in systems-based drug design.
    Full-text · Article · Sep 2011 · Trends in Pharmacological Sciences
  • [Show abstract] [Hide abstract]
    ABSTRACT: In order to productively infect a host, viruses must enter the cell and force host cell replication mechanisms to produce new infectious virus particles. The success of this process unfortunately results in disease progression and, in the case of infection with many viral species, may cause mortality. The discoveries of Louis Pasteur and Edward Jenner led to one of the greatest advances in modern medicine - the development of vaccines that generate long-lasting memory immune responses to combat viral infection. Widespread use of vaccines has reduced mortality and morbidity associated with viral infection and, in some cases, has completely eradicated virus from the human population. Unfortunately, several viral species maintain a significant ability to mutate and escape vaccine-induced immune responses. Thus, novel anti-viral agents are required for treatment and prevention of viral disease. Targeting proteases that are crucial in the viral life cycle has proven to be an effective method to control viral infection, and this avenue of investigation continues generate anti-viral treatments. Herein, we provide the reader with a brief history as well as a comprehensive review of the most recent advances in the design and synthesis of viral protease inhibitors.
    No preview · Article · Sep 2012 · Current pharmaceutical design
Show more