ArticleJournal of structural and functional genomics2011
Leveraging structure determination with fragment screening for infectious disease drug targets: MECP synthase from Burkholderia pseudomallei.
Article in Journal of structural and functional genomics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 20 citations in OpenAlex.
- Analysis of Burkholderia pseudomallei IspF in complex with sulfapyridine, sulfamonomethoxine, ethoxzolamide and acetazolamide.Acta crystallographica. Section F, Structural biology communications · 2025Article
- Structural and biophysical characterization of the Burkholderia pseudomallei IspF inhibitor L-tryptophan hydroxamate.Bioorganic & medicinal chemistry letters · 2021Article
- Crystal structure of IspF fromBioscience reports · 2018Article
- Synthesis and biological evaluation of pyrazolopyrimidines as potential antibacterial agents.Bioorganic & medicinal chemistry letters · 2015Article
- Article
- Crystal structures of IspF from Plasmodium falciparum and Burkholderia cenocepacia: comparisons inform antimicrobial drug target assessment.BMC structural biology · 2014Article
- Cytidine derivatives as IspF inhibitors of Burkolderia pseudomallei.Bioorganic & medicinal chemistry letters · 2013Article
- Combining functional and structural genomics to sample the essential Burkholderia structome.PloS one · 2013Article
- Significant reduction in errors associated with nonbonded contacts in protein crystal structures: automated all-atom refinement with PrimeX.Acta crystallographica. Section D, Biological crystallography · 2012Article
- Structural genomics of infectious disease drug targets: the SSGCID.Acta crystallographica. Section F, Structural biology and crystallization communications · 2011Article
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
As part of the Seattle Structural Genomics Center for Infectious Disease, we seek to enhance structural genomics with ligand-bound structure data which can serve as a blueprint for structure-based drug design. We have adapted fragment-based screening methods to our structural genomics pipeline to generate multiple ligand-bound structures of high priority drug targets from pathogenic organisms. In this study, we report fragment screening methods and structure determination results for 2C-methyl-D-erythritol-2,4-cyclo-diphosphate (MECP) synthase from Burkholderia pseudomallei, the gram-negative bacterium which causes melioidosis. Screening by nuclear magnetic resonance spectroscopy as well as crystal soaking followed by X-ray diffraction led to the identification of several small molecules which bind this enzyme in a critical metabolic pathway. A series of complex structures obtained with screening hits reveal distinct binding pockets and a range of small molecules which form complexes with the target. Additional soaks with these compounds further demonstrate a subset of fragments to only bind the protein when present in specific combinations. This ensemble of fragment-bound complexes illuminates several characteristics of MECP synthase, including a previously unknown binding surface external to the catalytic active site. These ligand-bound structures now serve to guide medicinal chemists and structural biologists in rational design of novel inhibitors for this enzyme.
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