9B4G

Structure of inhibitor-bound human PSS1

これはPDB形式変換不可エントリーです。

9B4G の概要

• エントリーDOI: 10.2210/pdb9b4g/pdb
• EMDBエントリー: 44180
• 分子名称: Phosphatidylserine synthase 1, O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, ... (8 entities in total)
• 機能のキーワード: membrane protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 107342.85

構造登録者

Long, T.,Li, X. (登録日: 2024-03-20, 公開日: 2024-09-04, 最終更新日: 2024-10-23)

主引用文献

Long, T.,Li, D.,Vale, G.,Jiang, Y.,Schmiege, P.,Yang, Z.J.,McDonald, J.G.,Li, X.
Molecular insights into human phosphatidylserine synthase 1 reveal its inhibition promotes LDL uptake.
Cell, 187:5665-5678.e18, 2024

PubMed Abstract: In mammalian cells, two phosphatidylserine (PS) synthases drive PS synthesis. Gain-of-function mutations in the Ptdss1 gene lead to heightened PS production, causing Lenz-Majewski syndrome (LMS). Recently, pharmacological inhibition of PSS1 has been shown to suppress tumorigenesis. Here, we report the cryo-EM structures of wild-type human PSS1 (PSS1), the LMS-causing Pro269Ser mutant (PSS1), and PSS1 in complex with its inhibitor DS55980254. PSS1 contains 10 transmembrane helices (TMs), with TMs 4-8 forming a catalytic core in the luminal leaflet. These structures revealed a working mechanism of PSS1 akin to the postulated mechanisms of the membrane-bound O-acyltransferase family. Additionally, we showed that both PS and DS55980254 can allosterically inhibit PSS1 and that inhibition by DS55980254 activates the SREBP pathways, thus enhancing the expression of LDL receptors and increasing cellular LDL uptake. This work uncovers a mechanism of mammalian PS synthesis and suggests that selective PSS1 inhibitors have the potential to lower blood cholesterol levels.

PubMed: 39208797
DOI: 10.1016/j.cell.2024.08.004

実験手法

ELECTRON MICROSCOPY (2.87 Å)