4JLJ

Human dCK C4S-S74E mutant in complex with UDP and the F2.1.1 inhibitor (2-[({2-[3-(2-FLUOROETHOXY)-4-METHOXYPHENYL]-1,3-THIAZOL-4-YL}METHYL)SULFANYL]PYRIMIDINE-4,6-DIAMINE)

Summary for 4JLJ

• Entry DOI: 10.2210/pdb4jlj/pdb
• Related: 4JLK 4JLM
• Descriptor: Deoxycytidine kinase, 2-[({2-[3-(2-fluoroethoxy)-4-methoxyphenyl]-1,3-thiazol-4-yl}methyl)sulfanyl]pyrimidine-4,6-diamine, URIDINE-5'-DIPHOSPHATE, ... (4 entities in total)
• Functional Keywords: phosphoryl transfer, phosphorylation, kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P27707
• Total number of polymer chains: 2
• Total formula weight: 67841.52

Authors

Nomme, J.,Lavie, A. (deposition date: 2013-03-12, release date: 2014-01-22, Last modification date: 2023-09-20)

Primary citation

Nomme, J.,Murphy, J.M.,Su, Y.,Sansone, N.D.,Armijo, A.L.,Olson, S.T.,Radu, C.,Lavie, A.
Structural characterization of new deoxycytidine kinase inhibitors rationalizes the affinity-determining moieties of the molecules.
Acta Crystallogr.,Sect.D, 70:68-78, 2014

PubMed Abstract: Deoxycytidine kinase (dCK) is a key enzyme in the nucleoside salvage pathway that is also required for the activation of several anticancer and antiviral nucleoside analog prodrugs. Additionally, dCK has been implicated in immune disorders and has been found to be overexpressed in several cancers. To allow the probing and modulation of dCK activity, a new class of small-molecule inhibitors of the enzyme were developed. Here, the structural characterization of four of these inhibitors in complex with human dCK is presented. The structures reveal that the compounds occupy the nucleoside-binding site and bind to the open form of dCK. Surprisingly, a slight variation in the nature of the substituent at the 5-position of the thiazole ring governs whether the active site of the enzyme is occupied by one or two inhibitor molecules. Moreover, this substituent plays a critical role in determining the affinity, improving it from >700 to 1.5 nM in the best binder. These structures lay the groundwork for future modifications that would result in even tighter binding and the correct placement of moieties that confer favorable pharmacodynamics and pharmacokinetic properties.

PubMed: 24419380
DOI: 10.1107/S1399004713025030

Experimental method

X-RAY DIFFRACTION (2 Å)