|Entry||Database: PDB / ID: 7miv|
|Title||Mouse CTPS2-I250T bound to inhibitor R80|
|Components||CTP synthase 2CTP synthetase|
|Keywords||LIGASE / glutaminase / amidoligase / nucleotide metabolism|
|Function / homology|
Function and homology information
Interconversion of nucleotide di- and triphosphates / CTP synthase activity / cytoophidium / CTP synthase (glutamine hydrolysing) / 'de novo' CTP biosynthetic process / pyrimidine nucleobase biosynthetic process / CTP biosynthetic process / glutamine metabolic process / mitochondrion / ATP binding ...Interconversion of nucleotide di- and triphosphates / CTP synthase activity / cytoophidium / CTP synthase (glutamine hydrolysing) / 'de novo' CTP biosynthetic process / pyrimidine nucleobase biosynthetic process / CTP biosynthetic process / glutamine metabolic process / mitochondrion / ATP binding / identical protein binding / cytoplasm
Similarity search - Function
CTP synthase N-terminus / CTP synthase GATase domain / CTP synthase, N-terminal / CTP synthase / 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 2
Similarity search - Component
|Biological species||Mus musculus (house mouse)|
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 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
D: CTP synthase 2
C: CTP synthase 2
H: CTP synthase 2
G: CTP synthase 2
Mass: 65580.195 Da / Num. of mol.: 4 / Mutation: I250T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Ctps2 / Production host: Homo sapiens (human)
References: UniProt: P70303, CTP synthase (glutamine hydrolysing)
Type: L-peptide linking / Mass: 146.144 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C5H10N2O3
Mass: 484.141 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H15N2O15P3 / Comment: UTP*YM
Mass: 486.567 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H22N6O4S2 / Feature type: SUBJECT OF INVESTIGATION
|Has ligand of interest||Y|
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: FILAMENT / 3D reconstruction method: single particle reconstruction|
|Component||Name: mCTPS2-I250T tetramer / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT|
|Source (natural)||Organism: Mus musculus (house mouse)|
|Source (recombinant)||Organism: Homo sapiens (human)|
|Buffer solution||pH: 7.9|
|Specimen||Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|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|
|3D reconstruction||Resolution: 2.8 Å / Resolution method: FSC 0.5 CUT-OFF / Num. of particles: 75218 / Symmetry type: POINT|
-Feb 9, 2022. New format data for meta-information of EMDB entries
New format data for meta-information of EMDB entries
- Version 3 of the EMDB header file is now the official format.
- The previous official version 1.9 will be removed from the archive.
Related info.:EMDB header
External links:wwPDB to switch to version 3 of the EMDB data model
-Aug 12, 2020. Covid-19 info
New page: Covid-19 featured information page in EM Navigator.
Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data
+Mar 5, 2020. Novel coronavirus structure data
Novel coronavirus structure data
- International Committee on Taxonomy of Viruses (ICTV) defined the short name of the 2019 coronavirus as "SARS-CoV-2".
- The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2 - nature microbiology
- In the structure databanks used in Yorodumi, some data are registered as the other names, "COVID-19 virus" and "2019-nCoV". Here are the details of the virus and the list of structure data.
Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info
+Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)
EMDB accession codes are about to change! (news from PDBe EMDB page)
- The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
- The EM Navigator/Yorodumi systems omit the EMD- prefix.
Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator
+Jul 12, 2017. Major update of PDB
Major update of PDB
- wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
- This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
- In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
- Now, EM Navigator and Yorodumi are based on the updated data.
Thousand views of thousand structures
- Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
- This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
- The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.
Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi