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Structure paper

TitleStructural basis for isoform-specific inhibition of human CTPS1.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 118, Issue 40, Year 2021
Publish dateOct 5, 2021
AuthorsEric M Lynch / Michael A DiMattia / Steven Albanese / Gydo C P van Zundert / Jesse M Hansen / Joel D Quispe / Madison A Kennedy / Andreas Verras / Kenneth Borrelli / Angela V Toms / Neelu Kaila / Kevin D Kreutter / Joshua J McElwee / Justin M Kollman /
PubMed AbstractCytidine 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]) ...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.
External linksProc Natl Acad Sci U S A / PubMed:34583994 / PubMed Central
MethodsEM (single particle)
Resolution2.4 - 6.2 Å
Structure data

EMDB-23831, PDB-7mgz:
Human CTPS1 bound to UTP, AMPPNP, and glutamine
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-23832, PDB-7mh0:
Human CTPS1 bound to CTP
Method: EM (single particle) / Resolution: 6.2 Å

EMDB-23833, PDB-7mh1:
Human CTPS2 bound to CTP
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-23848, PDB-7mif:
Human CTPS1 bound to inhibitor R80
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-23850, PDB-7mig:
Human CTPS1 bound to inhibitor T35
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-23851, PDB-7mih:
Human CTPS2 bound to inhibitor R80
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-23852, PDB-7mii:
Human CTPS2 bound to inhibitor T35
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-23859, PDB-7mip:
Mouse CTPS1 bound to inhibitor R80
Method: EM (single particle) / Resolution: 2.4 Å

EMDB-23865, PDB-7miu:
Mouse CTPS2 bound to inhibitor R80
Method: EM (single particle) / Resolution: 2.6 Å

EMDB-23866, PDB-7miv:
Mouse CTPS2-I250T bound to inhibitor R80
Method: EM (single particle) / Resolution: 2.8 Å

Chemicals

ChemComp-UTP:
URIDINE 5'-TRIPHOSPHATE / UTP*YM / Uridine triphosphate

ChemComp-GLN:
GLUTAMINE / Glutamine

ChemComp-MG:
Unknown entry

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

ChemComp-CTP:
CYTIDINE-5'-TRIPHOSPHATE / Cytidine triphosphate

ChemComp-ZG4:
N-(1-{2-[(cyclopropanesulfonyl)amino]-1,3-thiazol-4-yl}cyclopropyl)-5-(6-ethoxypyrazin-2-yl)pyridine-2-carboxamide

ChemComp-ZFY:
2-{2-[(cyclopropanesulfonyl)amino]-1,3-thiazol-4-yl}-2-methyl-N-{5-[6-(trifluoromethyl)pyrazin-2-yl]pyridin-2-yl}propanamide

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsLIGASE / glutaminase / amidoligase / nucleotide metabolism

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