title: Structures of an alanine racemase from Bacillus anthracis (BA0252) in the presence and absence of (R)-1-aminoethylphosphonic acid (L-Ala-P).
abstract: Bacillus anthracis, the causative agent of anthrax, has been targeted by the Oxford Protein Production Facility to validate high-throughput protocols within the Structural Proteomics in Europe project. As part of this work, the structures of an alanine racemase (BA0252) in the presence and absence of the inhibitor (R)-1-aminoethylphosphonic acid (L-Ala-P) have determined by X-ray crystallography to resolutions of 2.1 and 1.47 A, respectively. Difficulties in crystallizing this protein were overcome by the use of reductive methylation. Alanine racemase has attracted much interest as a possible target for anti-anthrax drugs: not only is D-alanine a vital component of the bacterial cell wall, but recent studies also indicate that alanine racemase, which is accessible in the exosporium, plays a key role in inhibition of germination in B. anthracis. These structures confirm the binding mode of L-Ala-P but suggest an unexpected mechanism of inhibition of alanine racemase by this compound and could provide a basis for the design of improved alanine racemase inhibitors with potential as anti-anthrax therapies.
authors.affiliation: Oxford Protein Production Facility, The Henry Wellcome Building for Genomic Medicine, Oxford University, Roosevelt Drive, Oxford OX3 7BN, England.
authors.forename: Kinfai
authors.initials: K
authors.lastname: Au
authors.forename: Jingshan
authors.initials: J
authors.lastname: Ren
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Walter
authors.forename: Karl
authors.initials: K
authors.lastname: Harlos
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Nettleship
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Owens
authors.forename: David I
authors.initials: DI
authors.lastname: Stuart
authors.forename: Robert M
authors.initials: RM
authors.lastname: Esnouf
mesh_terms: D000411:Alanine Racemase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000615:Aminoethylphosphonic Acid / Q000494:pharmacology*; D001408:Bacillus anthracis / Q000187:drug effects / Q000201:enzymology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D008745:Methylation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013237:Stereoisomerism
chemical_list: D000615:Aminoethylphosphonic Acid; D000411:Alanine Racemase