3hij

Crystal structure of dihydrodipicolinate synthase from Bacillus anthracis in complex with its substrate, pyruvate

spinqualitylabelsall models 3hij, resolution 2.15Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3hij is a 4 chain structure with sequence from Bacillus anthracis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.15Å Ligands: GOL, KPI, NA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A6L7H340_BACAN Catalyzes the condensation of (S)-aspartate-beta-semialdehyde [(S)-ASA] and pyruvate to 4-hydroxy-tetrahydrodipicolinate (HTPA).[ARBA:ARBA00003294][HAMAP-Rule:MF_00418] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Bacillus anthracis is a gram-positive spore-forming bacterium that causes anthrax. With the increased threat of anthrax in biowarfare, there is an urgent need to characterize new antimicrobial targets from B. anthracis. One such target is dihydrodipicolinate synthase (DHDPS), which catalyzes the committed step in the pathway yielding meso-diaminopimelate and lysine. In this study, we employed CD spectroscopy to demonstrate that the thermostability of DHDPS from B. anthracis (Ba-DHDPS) is significantly enhanced in the presence of the substrate, pyruvate. Analytical ultracentrifugation studies show that the tetramer-dimer dissociation constant of the enzyme is 3-fold tighter in the presence of pyruvate compared with the apo form. To examine the significance of this substrate-mediated stabilization phenomenon, a dimeric mutant of Ba-DHDPS (L170E/G191E) was generated and shown to have markedly reduced activity compared with the wild-type tetramer. This demonstrates that the substrate, pyruvate, stabilizes the active form of the enzyme. We next determined the high resolution (2.15 A) crystal structure of Ba-DHDPS in complex with pyruvate (3HIJ) and compared this to the apo structure (1XL9). Structural analyses show that there is a significant (91 A(2)) increase in buried surface area at the tetramerization interface of the pyruvate-bound structure. This study describes a new mechanism for stabilization of the active oligomeric form of an antibiotic target from B. anthracis and reveals an "Achilles heel" that can be exploited in structure-based drug design. Substrate-mediated stabilization of a tetrameric drug target reveals Achilles heel in anthrax.,Voss JE, Scally SW, Taylor NL, Atkinson SC, Griffin MD, Hutton CA, Parker MW, Alderton MR, Gerrard JA, Dobson RC, Dogovski C, Perugini MA J Biol Chem. 2010 Feb 19;285(8):5188-95. Epub 2009 Nov 30. PMID:19948665 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dihydrodipicolinate synthase

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