title: Substrate Trapping in the Siderophore Tailoring Enzyme PvdQ.
abstract: Siderophore biosynthesis by Pseudomonas aeruginosa enhances virulence and represents an attractive drug target. PvdQ functions in the type-1 pyoverdine biosynthetic pathway by removing a myristoyl anchor from a pyoverdine precursor, allowing eventual release from the periplasm. A circularly permuted version of PvdQ bypasses the self-processing step of this Ntn-hydrolase and retains the activity, selectivity, and structure of wild-type PvdQ, as revealed by a 1.8 Å resolution X-ray crystal structure. A 2.55 Å resolution structure of the inactive S1A/N269D-cpPvdQ mutant in complex with the pyoverdine precursor PVDIq reveals a specific binding pocket for the d-Tyr of this modified peptide substrate. To our knowledge, this structure is the first of a pyoverdine precursor peptide bound to a biosynthetic enzyme. Details of the observed binding interactions have implications for control of pyoverdine biosynthesis and inform future drug design efforts.
authors.affiliation: Department of Chemistry, Northwestern University , Evanston, Illinois 60208, United States.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Clevenger
authors.affiliation: Department of Chemistry and Biochemistry, Loyola University Chicago , Chicago, Illinois 60660, United States.
authors.forename: Romila
authors.initials: R
authors.lastname: Mascarenhas
authors.affiliation: Department of Chemistry and Biochemistry, Loyola University Chicago , Chicago, Illinois 60660, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Catlin
authors.affiliation: Department of Chemistry and Biochemistry, Loyola University Chicago , Chicago, Illinois 60660, United States.
authors.forename: Rui
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Chemistry, Northwestern University , Evanston, Illinois 60208, United States.
authors.forename: Neil L
authors.identifier: 0000-0002-8815-3372
authors.initials: NL
authors.lastname: Kelleher
authors.affiliation: Hauptman-Woodward Medical Research Institute and Department of Structural Biology, SUNY University at Buffalo , Buffalo, New York 14203, United States.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Drake
authors.affiliation: Hauptman-Woodward Medical Research Institute and Department of Structural Biology, SUNY University at Buffalo , Buffalo, New York 14203, United States.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Gulick
authors.affiliation: Department of Chemistry and Biochemistry, Loyola University Chicago , Chicago, Illinois 60660, United States.
authors.forename: Dali
authors.initials: D
authors.lastname: Liu
authors.forename: Walter
authors.identifier: 0000-0001-7567-2213
authors.initials: W
authors.lastname: Fast
mesh_terms: D000581:Amidohydrolases / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D011487:Protein Conformation; D011550:Pseudomonas aeruginosa / Q000201:enzymology*; D017262:Siderophores / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D017262:Siderophores; D000581:Amidohydrolases; C438834:N-terminal nucleophile hydrolase