6EZJ

Imidazoleglycerol-phosphate dehydratase

6EZJ の概要

• エントリーDOI: 10.2210/pdb6ezj/pdb
• EMDBエントリー: 3999
• 分子名称: Imidazoleglycerol-phosphate dehydratase 2, chloroplastic, MANGANESE (II) ION, [(2R)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]phosphonic acid (3 entities in total)
• 機能のキーワード: inhibitor, histidine biosynthesis, lyase, complex
• 由来する生物種: Arabidopsis thaliana (Thale cress)
• タンパク質・核酸の鎖数: 24
• 化学式量合計: 544995.05

構造登録者

Rawson, S.,Bisson, C.,Hurdiss, D.L.,Muench, S.P. (登録日: 2017-11-15, 公開日: 2018-02-07, 最終更新日: 2024-05-15)

主引用文献

Rawson, S.,Bisson, C.,Hurdiss, D.L.,Fazal, A.,McPhillie, M.J.,Sedelnikova, S.E.,Baker, P.J.,Rice, D.W.,Muench, S.P.
Elucidating the structural basis for differing enzyme inhibitor potency by cryo-EM.
Proc. Natl. Acad. Sci. U.S.A., 115:1795-1800, 2018

PubMed Abstract: Histidine biosynthesis is an essential process in plants and microorganisms, making it an attractive target for the development of herbicides and antibacterial agents. Imidazoleglycerol-phosphate dehydratase (IGPD), a key enzyme within this pathway, has been biochemically characterized in both (IGPD) and (IGPD). The plant enzyme, having been the focus of in-depth structural analysis as part of an inhibitor development program, has revealed details about the reaction mechanism of IGPD, whereas the yeast enzyme has proven intractable to crystallography studies. The structure-activity relationship of potent triazole-phosphonate inhibitors of IGPD has been determined in both homologs, revealing that the lead inhibitor (C348) is an order of magnitude more potent against IGPD than IGPD; however, the molecular basis of this difference has not been established. Here we have used single-particle electron microscopy (EM) to study structural differences between the and IGPD homologs, which could influence the difference in inhibitor potency. The resulting EM maps at ∼3 Å are sufficient to de novo build the protein structure and identify the inhibitor binding site, which has been validated against the crystal structure of the IGPD/C348 complex. The structure of _IGPD reveals that a 24-amino acid insertion forms an extended loop region on the enzyme surface that lies adjacent to the active site, forming interactions with the substrate/inhibitor binding loop that may influence inhibitor potency. Overall, this study provides insights into the IGPD family and demonstrates the power of using an EM approach to study inhibitor binding.

PubMed: 29434040
DOI: 10.1073/pnas.1708839115

実験手法

ELECTRON MICROSCOPY (3.1 Å)