CRYSTALLOGRAPHIC STUDIES ON HUMAN DNA TOPOISOMERASE I

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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. Human DNA topoisomerase I (topo I) is an enzyme which relaxes helical strain in double-stranded DNA. Topo I has a critical role in DNA replication. It is also an attractive target for some anti-cancer drugs which inhibit the catalytic mechanism of topo I. We have recently determined the structures of ternary complexes of topo I with its substrate DNA and anti-cancer drugs. Topo I crystals generally diffract very weakly. We request synchrotron beamtime for X-ray diffraction data collection on additional topo I complex crystals for our ongoing design and development of novel topo I inhibitors.