7SQL

Crystal structure of human uridine-cytidine kinase 2 complexed with a weak small molecule inhibitor

7SQL の概要

• エントリーDOI: 10.2210/pdb7sql/pdb
• 分子名称: Uridine-cytidine kinase 2, TRIETHYLENE GLYCOL, GLYCEROL, ... (7 entities in total)
• 機能のキーワード: kinase, uridine kinase, cytidine kinase, inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 114759.47

構造登録者

Mashayekh, S.,Stunkard, L.M.,Kienle, M.,Mathews, I.I.,Khosla, C. (登録日: 2021-11-05, 公開日: 2022-10-12, 最終更新日: 2023-10-25)

主引用文献

Mashayekh, S.,Stunkard, L.M.,Kienle, M.,Mathews, I.I.,Khosla, C.
Structure-Based Prototyping of Allosteric Inhibitors of Human Uridine/Cytidine Kinase 2 (UCK2).
Biochemistry, 61:2261-2266, 2022

PubMed Abstract: Pyrimidine nucleotide biosynthesis in humans is a promising chemotherapeutic target for infectious diseases caused by RNA viruses. Because mammalian cells derive pyrimidine ribonucleotides through a combination of biosynthesis and salvage, combined inhibition of dihydroorotate dehydrogenase (DHODH; the first committed step in pyrimidine nucleotide biosynthesis) and uridine/cytidine kinase 2 (UCK2; the first step in salvage of exogenous nucleosides) strongly attenuates viral replication in infected cells. However, while several pharmacologically promising inhibitors of human DHODH are known, to date there are no reports of medicinally viable leads against UCK2. Here, we use structure-based drug prototyping to identify two classes of promising leads that noncompetitively inhibit UCK2 activity. In the process, we have identified a hitherto unknown allosteric site at the intersubunit interface of this homotetrameric enzyme. By reducing the of human UCK2 without altering its , these new inhibitors have the potential to enable systematic dialing of the fractional inhibition of pyrimidine salvage to achieve the desired antiviral effect with minimal host toxicity.

PubMed: 36190114
DOI: 10.1021/acs.biochem.2c00451

実験手法

X-RAY DIFFRACTION (2.4 Å)