CRYSTAL STRUCTURES OF POLYKETIDE SYNTHASES: STRUCTURE-BASED DRUG DESIGN OF NOVEL

Stanford University, Stanford CA

Investigators

Linked publications & trials

Abstract

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. Polyketides are a structurally diverse class of natural products that exhibit a diverse range of pharmacologically relevant activities including anti-cancer, antibiotic, anti-virus, and immunosuppressive properties, accounting for $ 30 billion of the worldwide pharmaceutical market in 2005. They are synthesized in nature from a limited repertoire of simple carboxylic acids by multifunctional proteins called polyketide synthases (PKSs). Type I PKSs, the target of the current study have a modular architecture. Determination of crystal structures of PKSs will greatly aid in systematically exploring the architectural features of the system and yield key insights into critical features such as domain boundary and substrate selectivity. This would in turn allow modification of PKSs by protein-engineering or substrate-engineering to produce the next generation of "unnatural" polyketide products. In the recent past we have solved the crystal structure of a 194 kDa homodimeric fragment of the 6-deoxyerythronolide B synthase(6-DEBS), in addition to the crystal structures of two thioesterases from 6-DEBS and picromycin polyketide synthase respectively and the crystal structure of priming ketosynthase (ZhuH) from R1128 polyketide synthase solved earlier utilizing the beamtime at SSRL. Given the importance of the polyketides in synthetic organic chemistry and drug discovery, solving the crystal structures of these proteins is only the beginning of structure-based drug design utilizing PKSs with the ultimate goal of accessing a variety of synthetic analogs which would serve as a library of macrocycle drug leads. In continuation with our studies on the structure of these proteins, beamtime at SSRL will be utilized to solve the crystal structures of a ketosynthase (KS)-acyl carrier protein (ACP) protein fragment which will be obtained via irreversible covalent cross-linking of the 2 individual domains from module 3 DEBS.