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In work that could streamline drug discovery, a new approach has been used to study cytochrome P450 flexibility. Human cytochromes P450 affect the duration of action and rates of body clearance of drugs and are thus of major interest in drug discovery. Unlike conventional enzymes, they metabolize widely variable substrates, but details about how they do this have been lacking. Bilikallahalli K. Muralidhara and Yonghong Zhao of the University of Texas Medical Branch (UTMB), Galveston, and coworkers have now used isothermal titration calorimetry for the first time, in conjunction with a P450-substrate crystal structure (shown), to probe the thermodynamics of P450 plasticity (J. Biol. Chem., published online Dec. 21, 2005, and Jan. 26, dx.doi.org/10.1074/jbc.M511464200 and M509696200). Among other findings, the studies reveal key roles played by two helices in enabling P450 to accommodate different sizes of ligands and yet maintain its overall fold. The study "dramatically alters the way we understand and analyze P450 flexibility," and isothermal titration calorimetry could thus "become a benchmark tool in the drug industry," says coauthor James R. Halpert, also of UTMB.
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