3MJR

Human dCK complex with Acyclic Nucleoside

Summary for 3MJR

• Entry DOI: 10.2210/pdb3mjr/pdb
• Descriptor: Deoxycytidine kinase, 9-HYROXYETHOXYMETHYLGUANINE, URIDINE-5'-DIPHOSPHATE, ... (4 entities in total)
• Functional Keywords: acv, gcv, dck, kinase, udp, p-loop, kinase activity, nucleoside kinase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : P27707
• Total number of polymer chains: 4
• Total formula weight: 132582.30

Authors

Hazra, S.,Lavie, A. (deposition date: 2010-04-13, release date: 2010-07-28, Last modification date: 2023-09-06)

Primary citation

Hazra, S.,Konrad, M.,Lavie, A.
The Sugar Ring of the Nucleoside Is Required for Productive Substrate Positioning in the Active Site of Human Deoxycytidine Kinase (dCK): Implications for the Development of dCK-Activated Acyclic Guanine Analogues.
J.Med.Chem., 53:5792-5800, 2010

PubMed Abstract: The low toxicity of acyclovir (ACV) is mainly due to the fact that human nucleoside kinases have undetectable phosphorylation rates with this acyclic guanine analogue. In contrast, herpes virus thymidine kinase (HSV1-TK) readily activates ACV. We wanted to understand why human deoxycytidine kinase (dCK), which is related to HSV1-TK and phosphorylates deoxyguanosine, does not accept acyclic guanine analogues as substrates. Therefore, we crystallized dCK in complex with ACV at the nucleoside phosphoryl acceptor site and UDP at the phosphoryl donor site. The structure reveals that while ACV does bind at the dCK active site, it does so adopting a nonproductive conformation. Despite binding ACV, the enzyme remains in the open, inactive state. In comparison to ACV binding to HSV1-TK, in dCK, the nucleoside base adopts a different orientation related by about a 60 degrees rotation. Our analysis suggests that dCK would phosphorylate acyclic guanine analogues if they can induce a similar rotation.

PubMed: 20684612
DOI: 10.1021/jm1005379

Experimental method

X-RAY DIFFRACTION (2.1 Å)