5H39

Structural analysis of KSHV thymidylate synthase

Summary for 5H39

• Entry DOI: 10.2210/pdb5h39/pdb
• Related: 5H38 5H3A
• Descriptor: ORF70, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE (3 entities in total)
• Functional Keywords: thymidylate synthase, inhibitor, raltitrexed, dump, transferase
• Biological source: Human herpesvirus 8 (HHV-8)
• Total number of polymer chains: 2
• Total formula weight: 66377.74

Authors

Choi, Y.M.,Yeo, H.K.,Park, Y.W.,Lee, J.Y. (deposition date: 2016-10-21, release date: 2017-01-18, Last modification date: 2023-11-08)

Primary citation

Choi, Y.M.,Yeo, H.K.,Park, Y.W.,Lee, J.Y.
Structural Analysis of Thymidylate Synthase from Kaposi's Sarcoma-Associated Herpesvirus with the Anticancer Drug Raltitrexed.
PLoS ONE, 11:e0168019-e0168019, 2016

PubMed Abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is a highly infectious human herpesvirus that causes Kaposi's sarcoma. KSHV encodes functional thymidylate synthase, which is a target for anticancer drugs such as raltitrexed or 5-fluorouracil. Thymidylate synthase catalyzes the conversion of 2'-deoxyuridine-5'-monophosphate (dUMP) to thymidine-5'-monophosphate (dTMP) using 5,10-methylenetetrahydrofolate (mTHF) as a co-substrate. The crystal structures of thymidylate synthase from KSHV (apo), complexes with dUMP (binary), and complexes with both dUMP and raltitrexed (ternary) were determined at 1.7 Å, 2.0 Å, and 2.4 Å, respectively. While the ternary complex structures of human thymidylate synthase and E. coli thymidylate synthase had a closed conformation, the ternary complex structure of KSHV thymidylate synthase was observed in an open conformation, similar to that of rat thymidylate synthase. The complex structures of KSHV thymidylate synthase did not have a covalent bond between the sulfhydryl group of Cys219 and C6 atom of dUMP, unlike the human thymidylate synthase. The catalytic Cys residue demonstrated a dual conformation in the apo structure, and its sulfhydryl group was oriented toward the C6 atom of dUMP with no covalent bond upon ligand binding in the complex structures. These structural data provide the potential use of antifolates such as raltitrexed as a viral induced anticancer drug and structural basis to design drugs for targeting the thymidylate synthase of KSHV.

PubMed: 27936107
DOI: 10.1371/journal.pone.0168019

Experimental method

X-RAY DIFFRACTION (2 Å)