5AYZ

CRYSTAL STRUCTURE OF HUMAN QUINOLINATE PHOSPHORIBOSYLTRANSFERASE IN COMPLEX WITH THE PRODUCT NICOTINATE MONONUCLEOTIDE

「4R3Y」から置き換えられました

5AYZ の概要

• エントリーDOI: 10.2210/pdb5ayz/pdb
• 関連するPDBエントリー: 4R3X
• 分子名称: Nicotinate-nucleotide pyrophosphorylase [carboxylating], NICOTINATE MONONUCLEOTIDE (3 entities in total)
• 機能のキーワード: transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 387022.19

構造登録者

Youn, H.S.,Kim, T.G.,Kim, M.K.,Kang, G.B.,Kang, J.Y.,Seo, Y.J.,Lee, J.G.,An, J.Y.,Park, K.R.,Lee, Y.,Im, Y.J.,Lee, J.H.,Fukuoka, S.I.,Eom, S.H. (登録日: 2015-09-14, 公開日: 2016-02-03, 最終更新日: 2023-11-08)

主引用文献

Youn, H.S.,Kim, T.G.,Kim, M.K.,Kang, G.B.,Kang, J.Y.,Lee, J.G.,An, J.Y.,Park, K.R.,Lee, Y.,Im, Y.J.,Lee, J.H.,Eom, S.H.
Structural Insights into the Quaternary Catalytic Mechanism of Hexameric Human Quinolinate Phosphoribosyltransferase, a Key Enzyme in de novo NAD Biosynthesis
Sci Rep, 6:19681-19681, 2016

PubMed Abstract: Quinolinate phosphoribosyltransferase (QPRT) catalyses the production of nicotinic acid mononucleotide, a precursor of de novo biosynthesis of the ubiquitous coenzyme nicotinamide adenine dinucleotide. QPRT is also essential for maintaining the homeostasis of quinolinic acid in the brain, a possible neurotoxin causing various neurodegenerative diseases. Although QPRT has been extensively analysed, the molecular basis of the reaction catalysed by human QPRT remains unclear. Here, we present the crystal structures of hexameric human QPRT in the apo form and its complexes with reactant or product. We found that the interaction between dimeric subunits was dramatically altered during the reaction process by conformational changes of two flexible loops in the active site at the dimer-dimer interface. In addition, the N-terminal short helix α1 was identified as a critical hexamer stabilizer. The structural features, size distribution, heat aggregation and ITC studies of the full-length enzyme and the enzyme lacking helix α1 strongly suggest that human QPRT acts as a hexamer for cooperative reactant binding via three dimeric subunits and maintaining stability. Based on our comparison of human QPRT structures in the apo and complex forms, we propose a drug design strategy targeting malignant glioma.

PubMed: 26805589
DOI: 10.1038/srep19681

実験手法

X-RAY DIFFRACTION (2.6 Å)