8TD1

Structure of PYCR1 complexed with 3-(6-Oxa-9-azaspiro(4.5)decane-9-carbonyl)benzoic acid

8TD1 の概要

• エントリーDOI: 10.2210/pdb8td1/pdb
• 分子名称: Pyrroline-5-carboxylate reductase 1, mitochondrial, 3-(6-oxa-9-azaspiro[4.5]decane-9-carbonyl)benzoic acid, DI(HYDROXYETHYL)ETHER, ... (5 entities in total)
• 機能のキーワード: amino-acid biosynthesis, oxidoreductase, proline biosynthesis
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 169599.87

構造登録者

Tanner, J.J.,Meeks, K.R. (登録日: 2023-07-02, 公開日: 2024-03-06, 最終更新日: 2024-03-20)

主引用文献

Meeks, K.R.,Ji, J.,Protopopov, M.V.,Tarkhanova, O.O.,Moroz, Y.S.,Tanner, J.J.
Novel Fragment Inhibitors of PYCR1 from Docking-Guided X-ray Crystallography.
J.Chem.Inf.Model., 64:1704-1718, 2024

PubMed Abstract: The proline biosynthetic enzyme Δ-pyrroline-5-carboxylate (P5C) reductase 1 (PYCR1) is one of the most consistently upregulated enzymes across multiple cancer types and central to the metabolic rewiring of cancer cells. Herein, we describe a fragment-based, structure-first approach to the discovery of PYCR1 inhibitors. Thirty-seven fragment-like carboxylic acids in the molecular weight range of 143-289 Da were selected from docking and then screened using X-ray crystallography as the primary assay. Strong electron density was observed for eight compounds, corresponding to a crystallographic hit rate of 22%. The fragments are novel compared to existing proline analog inhibitors in that they block both the P5C substrate pocket and the NAD(P)H binding site. Four hits showed inhibition of PYCR1 in kinetic assays, and one has lower apparent IC than the current best proline analog inhibitor. These results show proof-of-concept for our inhibitor discovery approach and provide a basis for fragment-to-lead optimization.

PubMed: 38411104
DOI: 10.1021/acs.jcim.3c01879

実験手法

X-RAY DIFFRACTION (1.88 Å)