5BY6

Crystal structure of Trichinella spiralis thymidylate synthase complexed with dUMP

「4G9U」から置き換えられました

5BY6 の概要

• エントリーDOI: 10.2210/pdb5by6/pdb
• 分子名称: Thymidylate synthase, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, 2,3-DIHYDROXY-1,4-DITHIOBUTANE, ... (5 entities in total)
• 機能のキーワード: trichinella spiralis, parasitic nematode, protein-ligand complex, methyltransferase, transferase
• 由来する生物種: Trichinella spiralis (Trichina worm)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 144301.48

構造登録者

Dowiercial, A.,Jarmula, A.,Rypniewski, W.,Fraczyk, T.,Wilk, P.,Rode, W. (登録日: 2015-06-10, 公開日: 2015-06-17, 最終更新日: 2024-01-10)

主引用文献

Jarmula, A.,Wilk, P.,Maj, P.,Ludwiczak, J.,Dowiercial, A.,Banaszak, K.,Rypniewski, W.,Ciesla, J.,Dabrowska, M.,Fraczyk, T.,Bronowska, A.K.,Jakowiecki, J.,Filipek, S.,Rode, W.
Crystal structures of nematode (parasitic T. spiralis and free living C. elegans), compared to mammalian, thymidylate synthases (TS). Molecular docking and molecular dynamics simulations in search for nematode-specific inhibitors of TS.
J. Mol. Graph. Model., 77:33-50, 2017

PubMed Abstract: Three crystal structures are presented of nematode thymidylate synthases (TS), including Caenorhabditis elegans (Ce) enzyme without ligands and its ternary complex with dUMP and Raltitrexed, and binary complex of Trichinella spiralis (Ts) enzyme with dUMP. In search of differences potentially relevant for the development of species-specific inhibitors of the nematode enzyme, a comparison was made of the present Ce and Ts enzyme structures, as well as binary complex of Ce enzyme with dUMP, with the corresponding mammalian (human, mouse and rat) enzyme crystal structures. To complement the comparison, tCONCOORD computations were performed to evaluate dynamic behaviors of mammalian and nematode TS structures. Finally, comparative molecular docking combined with molecular dynamics and free energy of binding calculations were carried out to search for ligands showing selective affinity to T. spiralis TS. Despite an overall strong similarity in structure and dynamics of nematode vs mammalian TSs, a pool of ligands demonstrating predictively a strong and selective binding to TsTS has been delimited. These compounds, the E63 family, locate in the dimerization interface of TsTS where they exert species-specific interactions with certain non-conserved residues, including hydrogen bonds with Thr174 and hydrophobic contacts with Phe192, Cys191 and Tyr152. The E63 family of ligands opens the possibility of future development of selective inhibitors of TsTS and effective agents against trichinellosis.

PubMed: 28826032
DOI: 10.1016/j.jmgm.2017.08.008

実験手法

X-RAY DIFFRACTION (1.9 Å)