4FAI

Crystal structure of mitochondrial isoform of glutaminyl cyclase from Drosophila melanogaster

4FAI の概要

• エントリーDOI: 10.2210/pdb4fai/pdb
• 関連するPDBエントリー: 4F9U 4F9V 4FBE
• 分子名称: CG5976, isoform B, ZINC ION, 1-(3,4-dimethoxyphenyl)-3-[3-(1H-imidazol-1-yl)propyl]thiourea, ... (5 entities in total)
• 機能のキーワード: alpha/beta hydrolase, pglu formation, pe, alzheimer's disease, pyroglutamate, pglu-amyloid, transferase, hydrolase
• 由来する生物種: Drosophila melanogaster (Fruit fly)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 76703.15

構造登録者

Kolenko, P.,Koch, B.,Ruiz-Carilo, D.,Stubbs, M.T. (登録日: 2012-05-22, 公開日: 2012-08-29, 最終更新日: 2023-09-13)

主引用文献

Koch, B.,Kolenko, P.,Buchholz, M.,Ruiz Carrillo, D.,Parthier, C.,Wermann, M.,Rahfeld, J.U.,Reuter, G.,Schilling, S.,Stubbs, M.T.,Demuth, H.U.
Crystal Structures of Glutaminyl Cyclases (QCs) from Drosophila melanogaster Reveal Active Site Conservation between Insect and Mammalian QCs.
Biochemistry, 51:7383-7392, 2012

PubMed Abstract: Glutaminyl cyclases (QCs), which catalyze the formation of pyroglutamic acid (pGlu) at the N-terminus of a variety of peptides and proteins, have attracted particular attention for their potential role in Alzheimer's disease. In a transgenic Drosophila melanogaster (Dm) fruit fly model, oral application of the potent competitive QC inhibitor PBD150 was shown to reduce the burden of pGlu-modified Aβ. In contrast to mammals such as humans and rodents, there are at least three DmQC species, one of which (isoDromeQC) is localized to mitochondria, whereas DromeQC and an isoDromeQC splice variant possess signal peptides for secretion. Here we present the recombinant expression, characterization, and crystal structure determination of mature DromeQC and isoDromeQC, revealing an overall fold similar to that of mammalian QCs. In the case of isoDromeQC, the putative extended substrate binding site might be affected by the proximity of the N-terminal residues. PBD150 inhibition of DromeQC is roughly 1 order of magnitude weaker than that of the human and murine QCs. The inhibitor binds to isoDromeQC in a fashion similar to that observed for human QCs, whereas it adopts alternative binding modes in a DromeQC variant lacking the conserved cysteines near the active center and shows a disordered dimethoxyphenyl moiety in wild-type DromeQC, providing an explanation for the lower affinity. Our biophysical and structural data suggest that isoDromeQC and human QC are similar with regard to functional aspects. The two Dm enzymes represent a suitable model for further in-depth analysis of the catalytic mechanism of animal QCs, and isoDromeQC might serve as a model system for the structure-based design of potential AD therapeutics.

PubMed: 22897232
DOI: 10.1021/bi300687g

実験手法

X-RAY DIFFRACTION (1.65 Å)