[English] 日本語
Yorodumi
- EMDB-29281: Cryo-EM structure of STING oligomer bound to cGAMP and NVS-STG2 -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: EMDB / ID: EMD-29281
TitleCryo-EM structure of STING oligomer bound to cGAMP and NVS-STG2
Map dataMap of STING tetramer bound to cGAMP and NVS-STG2
Sample
  • Complex: STING tetramer
    • Protein or peptide: Stimulator of interferon genes protein
  • Ligand: cGAMPCyclic guanosine monophosphate–adenosine monophosphate
  • Ligand: 4-({[4-(2-tert-butyl-5,5-dimethyl-1,3-dioxan-2-yl)phenyl]methyl}amino)-3-methoxybenzoic acid
KeywordsSTING / innate immunity / molecular glue / IMMUNE SYSTEM
Function / homology
Function and homology information


STING complex / STAT6-mediated induction of chemokines / serine/threonine protein kinase complex / 2',3'-cyclic GMP-AMP binding / proton channel activity / cyclic-di-GMP binding / STING mediated induction of host immune responses / IRF3-mediated induction of type I IFN / cGAS/STING signaling pathway / positive regulation of type I interferon-mediated signaling pathway ...STING complex / STAT6-mediated induction of chemokines / serine/threonine protein kinase complex / 2',3'-cyclic GMP-AMP binding / proton channel activity / cyclic-di-GMP binding / STING mediated induction of host immune responses / IRF3-mediated induction of type I IFN / cGAS/STING signaling pathway / positive regulation of type I interferon-mediated signaling pathway / reticulophagy / pattern recognition receptor signaling pathway / cellular response to exogenous dsRNA / cytoplasmic pattern recognition receptor signaling pathway / autophagosome membrane / antiviral innate immune response / autophagosome assembly / positive regulation of macroautophagy / cellular response to organic cyclic compound / autophagosome / positive regulation of type I interferon production / cellular response to interferon-beta / signaling adaptor activity / positive regulation of defense response to virus by host / Regulation of innate immune responses to cytosolic DNA / activation of innate immune response / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of interferon-beta production / secretory granule membrane / cytoplasmic vesicle membrane / peroxisome / SARS-CoV-1 activates/modulates innate immune responses / positive regulation of DNA-binding transcription factor activity / protein complex oligomerization / positive regulation of protein binding / regulation of inflammatory response / defense response to virus / mitochondrial outer membrane / RNA polymerase II-specific DNA-binding transcription factor binding / endosome / Golgi membrane / innate immune response / ubiquitin protein ligase binding / Neutrophil degranulation / endoplasmic reticulum membrane / protein kinase binding / SARS-CoV-2 activates/modulates innate and adaptive immune responses / perinuclear region of cytoplasm / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / nucleoplasm / identical protein binding / plasma membrane / cytosol
Similarity search - Function
: / Stimulator of interferon genes protein / Stimulator of interferon genes protein, C-terminal domain superfamily / Transmembrane protein 173
Similarity search - Domain/homology
Stimulator of interferon genes protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.0 Å
AuthorsLi J / Canham SM / Zhang X / Bai X / Feng Y
Funding support United States, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM130289 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM143158 United States
Robert A. Welch FoundationI-1702 United States
Robert A. Welch FoundationI-1944 United States
CitationJournal: Nat Chem Biol / Year: 2024
Title: Activation of human STING by a molecular glue-like compound.
Authors: Jie Li / Stephen M Canham / Hua Wu / Martin Henault / Lihao Chen / Guoxun Liu / Yu Chen / Gary Yu / Howard R Miller / Viktor Hornak / Scott M Brittain / Gregory A Michaud / Antonin Tutter / ...Authors: Jie Li / Stephen M Canham / Hua Wu / Martin Henault / Lihao Chen / Guoxun Liu / Yu Chen / Gary Yu / Howard R Miller / Viktor Hornak / Scott M Brittain / Gregory A Michaud / Antonin Tutter / Wendy Broom / Mary Ellen Digan / Sarah M McWhirter / Kelsey E Sivick / Helen T Pham / Christine H Chen / George S Tria / Jeffery M McKenna / Markus Schirle / Xiaohong Mao / Thomas B Nicholson / Yuan Wang / Jeremy L Jenkins / Rishi K Jain / John A Tallarico / Sejal J Patel / Lianxing Zheng / Nathan T Ross / Charles Y Cho / Xuewu Zhang / Xiao-Chen Bai / Yan Feng /
Abstract: Stimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays a key role in the human innate immune response to infection and has been therapeutically exploited for its ...Stimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays a key role in the human innate immune response to infection and has been therapeutically exploited for its antitumor activity. The activation of STING requires its high-order oligomerization, which could be induced by binding of the endogenous ligand, cGAMP, to the cytosolic ligand-binding domain. Here we report the discovery through functional screens of a class of compounds, named NVS-STGs, that activate human STING. Our cryo-EM structures show that NVS-STG2 induces the high-order oligomerization of human STING by binding to a pocket between the transmembrane domains of the neighboring STING dimers, effectively acting as a molecular glue. Our functional assays showed that NVS-STG2 could elicit potent STING-mediated immune responses in cells and antitumor activities in animal models.
History
DepositionDec 21, 2022-
Header (metadata) releaseNov 1, 2023-
Map releaseNov 1, 2023-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: RCSB / Status: Released

-
Structure visualization

Supplemental images

emd_29281.png

Downloads & links

-
Map

FileDownload / File: emd_29281.map.gz / Format: CCP4 / Size: 15.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMap of STING tetramer bound to cGAMP and NVS-STG2
Voxel sizeX=Y=Z: 1.08 Å
Density
Contour LevelBy AUTHOR: 0.012
Minimum - Maximum-0.018094148 - 0.03851666
Average (Standard dev.)0.0005096205 (±0.0019860493)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions160160160
Spacing160160160
CellA=B=C: 172.8 Å
α=β=γ: 90.0 °

-
Supplemental data

-
Half map: half map 1

Fileemd_29281_half_map_1.map
Annotationhalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: half map 2

Fileemd_29281_half_map_2.map
Annotationhalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Sample components

-
Entire : STING tetramer

EntireName: STING tetramer
Components
  • Complex: STING tetramer
    • Protein or peptide: Stimulator of interferon genes protein
  • Ligand: cGAMPCyclic guanosine monophosphate–adenosine monophosphate
  • Ligand: 4-({[4-(2-tert-butyl-5,5-dimethyl-1,3-dioxan-2-yl)phenyl]methyl}amino)-3-methoxybenzoic acid

-
Supramolecule #1: STING tetramer

SupramoleculeName: STING tetramer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: STING tetramer, which can further assemblies into larger oligomers, induced by cGAMP and NVS-STG2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 300 KDa

-
Macromolecule #1: Stimulator of interferon genes protein

MacromoleculeName: Stimulator of interferon genes protein / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.553398 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPHSSLHPSI PCPRGHGAQK AALVLLSACL VTLWGLGEPP EHTLRYLVLH LASLQLGLLL NGVCSLAEEL RHIHSRYRGS YWRTVRACL GCPLRRGALL LLSIYFYYSL PNAVGPPFTW MLALLGLSQA LNILLGLKGL APAEISAVCE KGNFNVAHGL A WSYYIGYL ...String:
MPHSSLHPSI PCPRGHGAQK AALVLLSACL VTLWGLGEPP EHTLRYLVLH LASLQLGLLL NGVCSLAEEL RHIHSRYRGS YWRTVRACL GCPLRRGALL LLSIYFYYSL PNAVGPPFTW MLALLGLSQA LNILLGLKGL APAEISAVCE KGNFNVAHGL A WSYYIGYL RLILPELQAR IRTYNQHYNN LLRGAVSQRL YILLPLDCGV PDNLSMADPN IRFLDKLPQQ TGDRAGIKDR VY SNSIYEL LENGQRAGTC VLEYATPLQT LFAMSQYSQA GFSREDRLEQ AKLFCRTLED ILADAPESQN NCRLIAYQEP ADD SSFSLS QEVLRHLRQE EKEEVTVGTS SGLEVLFQ

UniProtKB: Stimulator of interferon genes protein

-
Macromolecule #2: cGAMP

MacromoleculeName: cGAMP / type: ligand / ID: 2 / Number of copies: 2 / Formula: 1SY
Molecular weightTheoretical: 674.411 Da
Chemical component information

ChemComp-1SY:
cGAMP / Cyclic guanosine monophosphate–adenosine monophosphate

-
Macromolecule #3: 4-({[4-(2-tert-butyl-5,5-dimethyl-1,3-dioxan-2-yl)phenyl]methyl}a...

MacromoleculeName: 4-({[4-(2-tert-butyl-5,5-dimethyl-1,3-dioxan-2-yl)phenyl]methyl}amino)-3-methoxybenzoic acid
type: ligand / ID: 3 / Number of copies: 2 / Formula: Y6H
Molecular weightTheoretical: 427.533 Da
Chemical component information

ChemComp-Y6H:
4-({[4-(2-tert-butyl-5,5-dimethyl-1,3-dioxan-2-yl)phenyl]methyl}amino)-3-methoxybenzoic acid

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
Sample preparation

BufferpH: 7.5
VitrificationCryogen name: NITROGEN

-
Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

-
Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

25142

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 117249
FSC plot (resolution estimation)

-
Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-8flk:
Cryo-EM structure of STING oligomer bound to cGAMP and NVS-STG2

+
About Yorodumi

-
News

-
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

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

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

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
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

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
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.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

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

Read more