6QYA

Crystal structure of Enteroccocus faecalis thymidylate synthase (EfTS) in complex with dUMP

Summary for 6QYA

• Entry DOI: 10.2210/pdb6qya/pdb
• Related: 6QXG 6QXH 6QXS
• Descriptor: Thymidylate synthase, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, 1,2-ETHANEDIOL, ... (8 entities in total)
• Functional Keywords: enteroccocus faecalis thymidylate synthase, efts, folate pathway, substrate, dump, transferase
• Biological source: Enterococcus faecalis; More
• Total number of polymer chains: 4
• Total formula weight: 148297.77

Authors

Pozzi, C.,Mangani, M. (deposition date: 2019-03-08, release date: 2019-04-10, Last modification date: 2024-01-24)

Primary citation

Pozzi, C.,Ferrari, S.,Luciani, R.,Tassone, G.,Costi, M.P.,Mangani, S.
Structural Comparison ofEnterococcus faecalisand Human Thymidylate Synthase Complexes with the Substrate dUMP and Its Analogue FdUMP Provides Hints about Enzyme Conformational Variabilities.
Molecules, 24:-, 2019

PubMed Abstract: Thymidylate synthase (TS) is an enzyme of paramount importance as it provides the only de novo source of deoxy-thymidine monophosphate (dTMP). dTMP, essential for DNA synthesis, is produced by the TS-catalyzed reductive methylation of 2'-deoxyuridine-5'-monophosphate (dUMP) using N⁵,N-methylenetetrahydrofolate (mTHF) as a cofactor. TS is ubiquitous and a validated drug target. TS enzymes from different organisms differ in sequence and structure, but are all obligate homodimers. The structural and mechanistic differences between the human and bacterial enzymes are exploitable to obtain selective inhibitors of bacterial TSs that can enrich the currently available therapeutic tools against bacterial infections. is a pathogen fully dependent on TS for dTMP synthesis. In this study, we present four new crystal structures of and human TSs in complex with either the substrate dUMP or the inhibitor FdUMP. The results provide new clues about the half-site reactivity of TS and the mechanisms underlying the conformational changes occurring in the two enzymes. We also identify relevant differences in cofactor and inhibitor binding between and human TS that can guide the design of selective inhibitors against bacterial TSs.

PubMed: 30935102
DOI: 10.3390/molecules24071257

Experimental method

X-RAY DIFFRACTION (1.76 Å)