3RDP

Crystal structure of thymidine kinase from herpes simplex virus type 1 in complex with N-METHYL-FHBT

Summary for 3RDP

• Entry DOI: 10.2210/pdb3rdp/pdb
• Related: 1E2H 1E2P 3F0T
• Descriptor: Thymidine kinase, SULFATE ION, 6-[(2R)-2-(fluoromethyl)-3-hydroxy-propyl]-1,5-dimethyl-pyrimidine-2,4-dione, ... (4 entities in total)
• Functional Keywords: transferase, thymidine kinase, dna-synthesis, pet tracer, atp-binding, dna synthesis, early protein, nucleotide-binding
• Biological source: Human herpesvirus 1 (HHV-1)
• Total number of polymer chains: 2
• Total formula weight: 72306.83

Authors

Pernot, L.,Perozzo, R.,Westermaier, Y.,Martic, M.,Ametamey, S.,Scapozza, L. (deposition date: 2011-04-01, release date: 2011-08-03, Last modification date: 2023-11-01)

Primary citation

Martic, M.,Pernot, L.,Westermaier, Y.,Perozzo, R.,Kraljevic, T.G.,Kristafor, S.,Raic-Malic, S.,Scapozza, L.,Ametamey, S.
Synthesis, crystal structure, and in vitro biological evaluation of C-6 pyrimidine derivatives: new lead structures for monitoring gene expression in vivo.
Nucleosides Nucleotides Nucleic Acids, 30:293-315, 2011

PubMed Abstract: Novel C-6 substituted pyrimidine derivatives are good substrates of herpes simplex virus type 1 thymidine kinase (HSV1-TK). Enzyme kinetic experiments showed that our lead compound, N-methyl DHBT (N-methyl-6-(1,3-dihydroxyisobutyl) thymine; N-Me DHBT), is phosphorylated at a similar rate compared to "gold standard" 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine, FHBG, (K(m) = 10 ± 0.3 μM; k(cat) = 0.036 ± 0.015 sec(-1)). Additionally, it does not show cytotoxic properties on B16F1 cells up to a concentration of 10 mM. The x-ray analysis of the crystal structures of HSV1-TK with N-Me DHBT and of HSV1-TK with the fluorinated derivative N-Me FHBT confirmed the binding mode predicted by docking studies and their substrate characteristics. Moreover, the crystal structure of HSV1-TK with N-Me DHBT revealed an additional water-mediated H-bond interesting for the design of further analogues.

PubMed: 21623543
DOI: 10.1080/15257770.2011.581258

Experimental method

X-RAY DIFFRACTION (2.8 Å)