HIGH RESOLUTION CRYSTALLOGRAPHY OF HEME ENZYMES WITH SUBSTRATE-LINKED SENSITIZER

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Currently there is substantial interest in the substrate access pathway and the conformational changes associated with substrate binding to P450s. To fully analyze these specific interactions, substrate-linked sensitizer (SLS) probes have been developed. To date, 1.55 and 1.65 ¿¿structures of ruthenium tris-bipyridyl probes bound to P450cam have been solved, along with 2.2, 1.8, and 1.45 ¿¿structures of fluorescent-based probes bound to P450cam. As the design process continues to optimize the SLS probes for spectroscopic studies and inhibitor identification, alternative fluorophores will be explored in a second generation of probes. Thus, the high-resolution crystallographic studies in this proposal will significantly aid in the long-term goal of developing enzyme-specific probes for analyzing the complex mechanisms of molecular recognition as well as for rapid screening of inhibitors of bio-medically important enzymes such as cytochrome P450s.