Download MendeleyLeveraging structure determination with fragment screening for infectious disease drug targets: MECP synthase from Burkholderia pseudomallei.
Begley, D.W., Hartley, R.C., Davies, D.R., Edwards, T.E., Leonard, J.T., Abendroth, J., Burris, C.A., Bhandari, J., Myler, P.J., Staker, B.L., Stewart, L.J.(2011) J Struct Funct Genomics 12: 63-76
- PubMed: 21359640
- DOI: https://doi.org/10.1007/s10969-011-9102-6
- Primary Citation of Related Structures:
3F0D, 3F0E, 3F0G, 3IEQ, 3IEW, 3IKE, 3IKF, 3JVH, 3K14, 3K2X, 3MBM, 3P0Z, 3P10, 3QHD - PubMed 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.
Organizational Affiliation:
Emerald BioStructures, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA. [email protected]
