7SQL
Crystal structure of human uridine-cytidine kinase 2 complexed with a weak small molecule inhibitor
Summary for 7SQL
| Entry DOI | 10.2210/pdb7sql/pdb |
| Descriptor | Uridine-cytidine kinase 2, TRIETHYLENE GLYCOL, GLYCEROL, ... (7 entities in total) |
| Functional Keywords | kinase, uridine kinase, cytidine kinase, inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 114759.47 |
| Authors | Mashayekh, S.,Stunkard, L.M.,Kienle, M.,Mathews, I.I.,Khosla, C. (deposition date: 2021-11-05, release date: 2022-10-12, Last modification date: 2023-10-25) |
| Primary citation | 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 Cited by 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: 36190114DOI: 10.1021/acs.biochem.2c00451 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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