8JAT

Crystal structure of the 3-ketodihydrosphingosine reductase TSC10 from Cryptococcus neoformans

8JAT の概要

• エントリーDOI: 10.2210/pdb8jat/pdb
• 分子名称: 3-ketodihydrosphingosine reductase TSC10, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (3 entities in total)
• 機能のキーワード: 3-ketodihydrosphingosine reductase, cryptococcus neoformans, oxidoreductase
• 由来する生物種: Cryptococcus neoformans var. neoformans JEC21
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 30514.33

構造登録者

Zhao, P.,Kuang, Z. (登録日: 2023-05-07, 公開日: 2023-06-21, 最終更新日: 2024-05-29)

主引用文献

Zhao, P.,Zhuang, Z.,Guan, X.,Yang, J.,Wang, W.,Kuang, Z.
Crystal structure of the 3-ketodihydrosphingosine reductase TSC10 from Cryptococcus neoformans.
Biochem.Biophys.Res.Commun., 670:73-78, 2023

PubMed Abstract: The second step in the de novo sphingolipid biosynthesis is the reduction of 3-ketodihydrosphingosine by 3-ketodihydrosphingosine reductase (KDSR) to produce dihydrosphingosine (sphinganine). Fungal TSC10 and mammalian KDSR (also named FVT-1) proteins are the enzymes responsible for this process and they belong to the short-chain dehydrogenase/reductase (SDR) superfamily. Albeit that both fungal and mammalian 3-ketodihydrosphingosine reductases were identified more than a decade ago, no structure of these enzymes from any species has been experimentally determined. Here we report the crystal structure of the catalytic domain of TSC10 from Cryptococcus neoformans in complex with NADPH. cnTSC10 adopts a Rossmann fold with a central seven-stranded β-sheet flanked by α-helices on both sides. Several regions are disordered that include the segment connecting the serine and tyrosine residues of the catalytic triad, the so-called 'substrate loop', and the C-terminal region that often participates in homo-tetramerization in other SDRs. In addition, the cofactor NADPH is not fully ordered. These structural features indicate that the catalytic site of cnTSC10 possesses significant flexibility. cnTSC10 is predominantly dimeric in solution while a minor portion of the protein forms homo-tetramer. The crystal structure reveals that the homo-dimer interface involves both hydrophobic and hydrophilic interactions mediated by helices α4 and α5, as well as the loop connecting strand β4 and helix α4. Because residues forming hydrogen bonds and salt bridges in the dimer interface are not conserved between fungal TSC10 and mammalian KDSR proteins, it might be possible to develop inhibitors that selectively target fungal TSC10 dimerization.

PubMed: 37285720
DOI: 10.1016/j.bbrc.2023.05.109

実験手法

X-RAY DIFFRACTION (3.2 Å)