ArticleThe Journal of biological chemistry2010
Substrate-mediated stabilization of a tetrameric drug target reveals Achilles heel in anthrax.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 46 citations in OpenAlex.
- A new lysine biosynthetic enzyme from a bacterial endosymbiont shaped by genetic drift and genome reduction.Protein science : a publication of the Protein Society · 2024Article
- Structure of the 4-hydroxy-tetrahydrodipicolinate synthase from the thermoacidophilic methanotroph Methylacidiphilum fumariolicum SolV and the phylogeny of the aminotransferase pathway.Acta crystallographica. Section F, Structural biology communications · 2020Article
- Characterization of recombinant dihydrodipicolinate synthase from the bread wheat Triticum aestivum.Planta · 2018Article
- Molecular evolution of an oligomeric biocatalyst functioning in lysine biosynthesis.Biophysical reviews · 2018Review
- Structure and Function of Cyanobacterial DHDPS and DHDPR.Scientific reports · 2016Article
- Dimerization of Bacterial Diaminopimelate Decarboxylase Is Essential for Catalysis.The Journal of biological chemistry · 2016Article
- Crystal structure and in silico studies of dihydrodipicolinate synthase (DHDPS) from Aquifex aeolicus.Extremophiles : life under extreme conditions · 2014Article
- Purification, crystallization and preliminary X-ray diffraction analysis of a novel keto-deoxy-D-galactarate (KDG) dehydratase from Agrobacterium tumefaciens.Acta crystallographica. Section F, Structural biology communications · 2014Article
- Cloning to crystallization of dihydrodipicolinate synthase from the intracellular pathogen Legionella pneumophila.Acta crystallographica. Section F, Structural biology and crystallization communications · 2013Article
- Dimerization of bacterial diaminopimelate epimerase is essential for catalysis.The Journal of biological chemistry · 2013Article
- Structural, kinetic and computational investigation of Vitis vinifera DHDPS reveals new insight into the mechanism of lysine-mediated allosteric inhibition.Plant molecular biology · 2013Article
- From knock-out phenotype to three-dimensional structure of a promising antibiotic target from Streptococcus pneumoniae.PloS one · 2013Article
- Cloning, expression, purification and crystallization of dihydrodipicolinate synthase from Agrobacterium tumefaciens.Acta crystallographica. Section F, Structural biology and crystallization communications · 2012Article
- Crystal, solution and in silico structural studies of dihydrodipicolinate synthase from the common grapevine.PloS one · 2012Article
- Structural and dynamic requirements for optimal activity of the essential bacterial enzyme dihydrodipicolinate synthase.PLoS computational biology · 2012Article
- Article
- Cloning, expression, purification and crystallization of dihydrodipicolinate synthase from the grapevine Vitis vinifera.Acta crystallographica. Section F, Structural biology and crystallization communications · 2011Article
- Crystallization and preliminary X-ray diffraction analysis of dihydrodipicolinate synthase 2 from Arabidopsis thaliana.Acta crystallographica. Section F, Structural biology and crystallization communications · 2011Article
- L,L-diaminopimelate aminotransferase from Chlamydomonas reinhardtii: a target for algaecide development.PloS one · 2011Article
- Cloning, expression, purification and crystallization of dihydrodipicolinate synthase from the psychrophile Shewanella benthica.Acta crystallographica. Section F, Structural biology and crystallization communications · 2010Article
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.