7MIG

Human CTPS1 bound to inhibitor T35

7MIG の概要

• エントリーDOI: 10.2210/pdb7mig/pdb
• EMDBエントリー: 23850
• 分子名称: CTP synthase 1, 2-{2-[(cyclopropanesulfonyl)amino]-1,3-thiazol-4-yl}-2-methyl-N-{5-[6-(trifluoromethyl)pyrazin-2-yl]pyridin-2-yl}propanamide, GLUTAMINE, ... (5 entities in total)
• 機能のキーワード: glutaminase, amidoligase, nucleotide metabolism, ligase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 271777.66

構造登録者

Lynch, E.M.,Dimattia, M.A.,Kollman, J.M. (登録日: 2021-04-16, 公開日: 2021-10-13, 最終更新日: 2024-11-13)

主引用文献

Lynch, E.M.,DiMattia, M.A.,Albanese, S.,van Zundert, G.C.P.,Hansen, J.M.,Quispe, J.D.,Kennedy, M.A.,Verras, A.,Borrelli, K.,Toms, A.V.,Kaila, N.,Kreutter, K.D.,McElwee, J.J.,Kollman, J.M.
Structural basis for isoform-specific inhibition of human CTPS1.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: Cytidine triphosphate synthase 1 (CTPS1) is necessary for an effective immune response, as revealed by severe immunodeficiency in CTPS1-deficient individuals [E. Martin ], [] [510], [288-292] ([2014]). CTPS1 expression is up-regulated in activated lymphocytes to expand CTP pools [E. Martin ], [] [510], [288-292] ([2014]), satisfying increased demand for nucleic acid and lipid synthesis [L. D. Fairbanks, M. Bofill, K. Ruckemann, H. A. Simmonds], [ ] [270], [29682-29689] ([1995]). Demand for CTP in other tissues is met by the CTPS2 isoform and nucleoside salvage pathways [E. Martin ], [] [510], [288-292] ([2014]). Selective inhibition of the proliferative CTPS1 isoform is therefore desirable in the treatment of immune disorders and lymphocyte cancers, but little is known about differences in regulation of the isoforms or mechanisms of known inhibitors. We show that CTP regulates both isoforms by binding in two sites that clash with substrates. CTPS1 is less sensitive to CTP feedback inhibition, consistent with its role in increasing CTP levels in proliferation. We also characterize recently reported small-molecule inhibitors, both CTPS1 selective and nonselective. Cryo-electron microscopy (cryo-EM) structures reveal these inhibitors mimic CTP binding in one inhibitory site, where a single amino acid substitution explains selectivity for CTPS1. The inhibitors bind to CTPS assembled into large-scale filaments, which for CTPS1 normally represents a hyperactive form of the enzyme [E. M. Lynch ], [] [24], [507-514] ([2017]). This highlights the utility of cryo-EM in drug discovery, particularly for cases in which targets form large multimeric assemblies not amenable to structure determination by other techniques. Both inhibitors also inhibit the proliferation of human primary T cells. The mechanisms of selective inhibition of CTPS1 lay the foundation for the design of immunosuppressive therapies.

PubMed: 34583994
DOI: 10.1073/pnas.2107968118

実験手法

ELECTRON MICROSCOPY (2.9 Å)