3JVH

Crystal structure of 2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase from Burkholderia pseudomallei with FOL fragment 8395

3JVH の概要

• エントリーDOI: 10.2210/pdb3jvh/pdb
• 関連するPDBエントリー: 3F0E 3F0G 3IEQ 3IEW 3IKE 3IKF
• 分子名称: 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase, ZINC ION, 5-[(pyridin-3-ylmethyl)amino]-1H-pyrazole-4-carboxamide, ... (5 entities in total)
• 機能のキーワード: niaid, ssgcid, seattle dtructural genomics center for infectious disease, fragment crystallography, fragments of life, zinc-binding fragment, isoprene biosynthesis, lyase, metal-binding, structural genomics, seattle structural genomics center for infectious disease
• 由来する生物種: Burkholderia pseudomallei (Pseudomonas pseudomallei)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 59401.33

構造登録者

Seattle Structural Genomics Center for Infectious Disease (SSGCID) (登録日: 2009-09-16, 公開日: 2009-09-29, 最終更新日: 2023-09-06)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.69 Å)