|Entry||Database: PDB / ID: 7mif|
|Title||Human CTPS1 bound to inhibitor R80|
|Components||CTP synthase 1|
|Keywords||LIGASE / glutaminase / amidoligase / nucleotide metabolism|
|Function / homology|
Function and homology information
cytoophidium / CTP synthase (glutamine hydrolysing) / CTP synthase activity / 'de novo' CTP biosynthetic process / pyrimidine nucleobase biosynthetic process / B cell proliferation / nucleobase-containing compound metabolic process / CTP biosynthetic process / Interconversion of nucleotide di- and triphosphates / glutamine metabolic process ...cytoophidium / CTP synthase (glutamine hydrolysing) / CTP synthase activity / 'de novo' CTP biosynthetic process / pyrimidine nucleobase biosynthetic process / B cell proliferation / nucleobase-containing compound metabolic process / CTP biosynthetic process / Interconversion of nucleotide di- and triphosphates / glutamine metabolic process / T cell proliferation / response to xenobiotic stimulus => GO:0009410 / membrane / ATP binding / identical protein binding / cytosol / cytoplasm
Similarity search - Function
CTP synthase / CTP synthase GATase domain / CTP synthase N-terminus / CTP synthase, N-terminal / Glutamine amidotransferase type 1 domain profile. / Glutamine amidotransferase class-I / Glutamine amidotransferase / Class I glutamine amidotransferase-like / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
GLUTAMINE / URIDINE 5'-TRIPHOSPHATE / Chem-ZG4 / CTP synthase 1
Similarity search - Component
|Biological species||Homo sapiens (human)|
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å|
|Authors||Lynch, E.M. / Dimattia, M.A. / Kollman, J.M.|
|Funding support|| United States, 1items |
|Citation||Journal: Proc Natl Acad Sci U S A / Year: 2021|
Title: Structural basis for isoform-specific inhibition of human CTPS1.
Authors: Eric 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 ...Authors: Eric 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 /
Abstract: Cytidine triphosphate synthase 1 (CTPS1) is necessary for an effective immune response, as revealed by severe immunodeficiency in CTPS1-deficient individuals [E. Martin ],  , [288-292] () ...Cytidine triphosphate synthase 1 (CTPS1) is necessary for an effective immune response, as revealed by severe immunodeficiency in CTPS1-deficient individuals [E. Martin ],  , [288-292] (). CTPS1 expression is up-regulated in activated lymphocytes to expand CTP pools [E. Martin ],  , [288-292] (), satisfying increased demand for nucleic acid and lipid synthesis [L. D. Fairbanks, M. Bofill, K. Ruckemann, H. A. Simmonds], [ ] , [29682-29689] (). Demand for CTP in other tissues is met by the CTPS2 isoform and nucleoside salvage pathways [E. Martin ],  , [288-292] (). 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 ],  , [507-514] (). 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.
|Structure viewer||Molecule: |
Downloads & links
C: CTP synthase 1
G: CTP synthase 1
H: CTP synthase 1
I: CTP synthase 1
Mass: 66777.297 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTPS1, CTPS / Production host: unidentified baculovirus
References: UniProt: P17812, CTP synthase (glutamine hydrolysing)
Type: L-peptide linking / Mass: 146.144 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C5H10N2O3
Mass: 486.567 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H22N6O4S2 / Feature type: SUBJECT OF INVESTIGATION
Mass: 484.141 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H15N2O15P3 / Comment: UTP*YM
|Has ligand of interest||Y|
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: FILAMENT / 3D reconstruction method: single particle reconstruction|
|Component||Name: CTPS1 tetramer / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT|
|Source (natural)||Organism: Homo sapiens (human)|
|Source (recombinant)||Organism: unidentified baculovirus|
|Buffer solution||pH: 7.9|
|Specimen||Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Specimen support||Grid material: COPPER / Grid type: C-flat-2/2|
|Vitrification||Cryogen name: ETHANE|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Model: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy|
|Image recording||Electron dose: 90 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)|
|CTF correction||Type: PHASE FLIPPING AND AMPLITUDE CORRECTION|
|Symmetry||Point symmetry: D2 (2x2 fold dihedral)|
|3D reconstruction||Resolution: 3.1 Å / Resolution method: FSC 0.5 CUT-OFF / Num. of particles: 117701 / Symmetry type: POINT|
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