CHAITAN KHOSLA PRT-CRYSTAL STRUCTURES OF POLYKETIDE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Polyketide synthase (PKS) produces a huge variety of anti-cancer, anti-virus, blood-pressure lowering and antibiotic compounds. No crystal structure has ever been determined for PKS. Determination of crystal structures of PKS will greatly facilitate the pharmaceutical utilization of PKS by protein-engineering or substrate-engineering. Eight critical enzymes of the polyketide synthase family has been crystalized, including ketosynthase/chain length factor (KS/CLF), aromatase (ARO), acyl carrier protein (ACP4), loading didomain (LDD), and various thioesterases (TE). Among these proteins, the structure of thioesterase (TE, proposal 5A42) has been solved to 2.8 ¿ utilizing the beamtime from SSRL. TEs from different species have also been crystallized, and will give us the chance to improve the resolution of TE. Of the remaining seven protein crystals, a ketosynthase (KS3) was found to give limited resolution (< 3.5 ¿) under the x-ray system in UCSF, and will greatly benefit from collecting data at SSRL.