Open AccessStructural basis for isoform-specific inhibition of human CTPS1
Author(s) -
E.M. Lynch,
Michael A. DiMattia,
Steven K. Albanese,
Gydo C. P. van Zundert,
Jesse M Hansen,
Joel Quispe,
Madison Kennedy,
Andreas Verras,
Kenneth Borrelli,
A.V. Toms,
Neelu Kaila,
Kevin D Kreutter,
Joshua McElwee,
Justin M. Kollman
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2107968118
Subject(s) - gene isoform , enzyme , biochemistry , chemistry , small molecule , nucleoside , biology , gene
Significance An effective immune response depends on the proliferation of T cells, a process that requires the enzyme CTP synthase 1 (CTPS1). Individuals lacking CTPS1 due to a rare genetic disorder exhibit severe immunodeficiencies but lack other major clinical consequences; the requirement for CTP synthase outside of the immune response is met by a second isoform, CTPS2. Inhibiting CTPS1 without affecting CTPS2 is therefore a promising strategy for treating autoimmune disorders and T cell cancers while avoiding off-target effects. We characterize both CTPS1-selective and nonselective inhibitors. Structures of CTPS bound to inhibitors reveal the mechanisms of inhibition and CTPS1 selectivity. Differences in product feedback inhibition between CTPS1 and CTPS2 explain how CTPS1 may sustain enzymatic activity required for T cell proliferation.