3QHD

Crystal structure of 2-C-METHYL-D-ERYTHRITOL 2,4-CYCLODIPHOSPHATE Synthase from BURKHOLDERIA PSEUDOMALLEI bound to CYTIDINE, FOL795 and FOL955

Summary for 3QHD

• Entry DOI: 10.2210/pdb3qhd/pdb
• Related: 3f0d 3ieq 3ike 3mbm 3p0z 3p10
• Descriptor: 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase, ZINC ION, CHLORIDE ION, ... (8 entities in total)
• Functional Keywords: seattle structural genomics center for infectious disease, ssgcid, ispf, cytidine, fol795, fol955, mep pathway, lyase, metal-binding
• Biological source: Burkholderia pseudomallei
• Total number of polymer chains: 3
• Total formula weight: 59812.15

Authors

Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2011-01-25, release date: 2011-02-09, Last modification date: 2023-09-13)

Primary citation

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.
Leveraging structure determination with fragment screening for infectious disease drug targets: MECP synthase from Burkholderia pseudomallei.
J Struct Funct Genomics, 12:63-76, 2011

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.

PubMed: 21359640
DOI: 10.1007/s10969-011-9102-6

Experimental method

X-RAY DIFFRACTION (1.7 Å)