3O84

Structure of BasE N-terminal domain from Acinetobacter baumannii bound to 6-phenyl-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid.

Summary for 3O84

• Entry DOI: 10.2210/pdb3o84/pdb
• Related: 3O82 3O83
• Descriptor: Peptide arylation enzyme, 6-phenyl-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid, CALCIUM ION, ... (7 entities in total)
• Functional Keywords: ligase, adenylation of 2, 3-dihydroxybenzoate and transfer to pantetheine cofactor of basf, non-ribosomal peptide synthetase (nrps)
• Biological source: Acinetobacter baumannii
• Total number of polymer chains: 2
• Total formula weight: 122944.05

Authors

Drake, E.J.,Duckworth, B.P.,Neres, J.,Aldrich, C.C.,Gulick, A.M. (deposition date: 2010-08-02, release date: 2010-10-06, Last modification date: 2023-09-06)

Primary citation

Drake, E.J.,Duckworth, B.P.,Neres, J.,Aldrich, C.C.,Gulick, A.M.
Biochemical and structural characterization of bisubstrate inhibitors of BasE, the self-standing nonribosomal peptide synthetase adenylate-forming enzyme of acinetobactin synthesis.
Biochemistry, 49:9292-9305, 2010

PubMed Abstract: The human pathogen Acinetobacter baumannii produces a siderophore called acinetobactin that is derived from one molecule each of threonine, histidine, and 2,3-dihydroxybenzoic acid (DHB). The activity of several nonribosomal peptide synthetase (NRPS) enzymes is used to combine the building blocks into the final molecule. The acinetobactin synthesis pathway initiates with a self-standing adenylation enzyme, BasE, that activates the DHB molecule and covalently transfers it to the pantetheine cofactor of an aryl-carrier protein of BasF, a strategy that is shared with many siderophore-producing NRPS clusters. In this reaction, DHB reacts with ATP to form the aryl adenylate and pyrophosphate. In a second partial reaction, the DHB is transferred to the carrier protein. Inhibitors of BasE and related enzymes have been identified that prevent growth of bacteria on iron-limiting media. Recently, a new inhibitor of BasE has been identified via high-throughput screening using a fluorescence polarization displacement assay. We present here biochemical and structural studies to examine the binding mode of this inhibitor. The kinetics of the wild-type BasE enzyme is shown, and inhibition studies demonstrate that the new compound exhibits competitive inhibition against both ATP and 2,3-dihydroxybenzoate. Structural examination of BasE bound to this inhibitor illustrates a novel binding mode in which the phenyl moiety partially fills the enzyme pantetheine binding tunnel. Structures of rationally designed bisubstrate inhibitors are also presented.

PubMed: 20853905
DOI: 10.1021/bi101226n

Experimental method

X-RAY DIFFRACTION (2.1 Å)