title: Structural basis for binding specificity between subclasses of modular polyketide synthase docking domains.
abstract: Bacterial type I polyketide synthases (PKSs) assemble structurally diverse natural products of significant clinical value from simple metabolic building blocks. The synthesis of these compounds occurs in a processive fashion along a large multiprotein complex. Transfer of the acyl intermediate across interpolypeptide junctions is mediated, at least in large part, by N- and C-terminal docking domains. We report here a comprehensive analysis of the binding affinity and selectivity for the complete set of discrete docking domain pairs in the pikromycin and erythromycin PKS systems. Despite disconnection from their parent module, each cognate pair of docking domains retained exquisite binding selectivity. Further insights were obtained by X-ray crystallographic analysis of the PikAIII/PikAIV docking domain interface. This new information revealed a series of key interacting residues that enabled development of a structural model for the recently proposed H2-T2 class of polypeptides involved in PKS intermodular molecular recognition.
authors.affiliation: Life Sciences Institute, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Tonia J
authors.initials: TJ
authors.lastname: Buchholz
authors.forename: Todd W
authors.initials: TW
authors.lastname: Geders
authors.forename: Frank E
authors.initials: FE
authors.lastname: Bartley
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Reynolds
authors.forename: Janet L
authors.initials: JL
authors.lastname: Smith
authors.forename: David H
authors.initials: DH
authors.lastname: Sherman
mesh_terms: D000595:Amino Acid Sequence; D001419:Bacteria / Q000201:enzymology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004917:Erythromycin / Q000737:chemistry / Q000378:metabolism*; D004926:Escherichia coli / Q000235:genetics; D005454:Fluorescence Polarization; D018942:Macrolides / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D048630:Polyketide Synthases / Q000737:chemistry* / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D013379:Substrate Specificity; D020349:Surface Plasmon Resonance
chemical_list: D018942:Macrolides; D004917:Erythromycin; D048630:Polyketide Synthases; C003145:picromycin