3K14

Co-crystal structure of 2C-methyl-D-erythritol 2,4-cyclodiphosphate synthase from Burkholderia pseudomallei with FOL fragment 535, ethyl 3-methyl-5,6-dihydroimidazo[2,1-b][1,3]thiazole-2-carboxylate

Summary for 3K14

• Entry DOI: 10.2210/pdb3k14/pdb
• Related: 3F0E 3F0G 3IEQ 3IKE 3IKF 3JVH
• Descriptor: 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase, ZINC ION, ethyl 3-methyl-5,6-dihydroimidazo[2,1-b][1,3]thiazole-2-carboxylate, ... (7 entities in total)
• Functional Keywords: niaid, ssgcid, seattle structural genomics center for infectious disease, fragment crystallography, fragment-based drug-design, fbdd, fragments of life, isoprene biosynthesis, lyase, metal-binding
• Biological source: Burkholderia pseudomallei (Pseudomonas pseudomallei)
• Total number of polymer chains: 3
• Total formula weight: 59421.91

Authors

Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2009-09-25, release date: 2009-10-06, Last modification date: 2024-02-21)

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)