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Yorodumi- EMDB-29282: Cryo-EM structure of STING oligomer bound to cGAMP, NVS-STG2 and C53 -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-29282 | |||||||||||||||
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Title | Cryo-EM structure of STING oligomer bound to cGAMP, NVS-STG2 and C53 | |||||||||||||||
Map data | ||||||||||||||||
Sample |
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Keywords | STING / innate immunity / molecular glue / IMMUNE SYSTEM | |||||||||||||||
Function / homology | Function and homology information STING complex / STAT6-mediated induction of chemokines / protein localization to endoplasmic reticulum / serine/threonine protein kinase complex / proton channel activity / 2',3'-cyclic GMP-AMP binding / STING mediated induction of host immune responses / cyclic-di-GMP binding / IRF3-mediated induction of type I IFN / positive regulation of type I interferon-mediated signaling pathway ...STING complex / STAT6-mediated induction of chemokines / protein localization to endoplasmic reticulum / serine/threonine protein kinase complex / proton channel activity / 2',3'-cyclic GMP-AMP binding / STING mediated induction of host immune responses / cyclic-di-GMP binding / IRF3-mediated induction of type I IFN / positive regulation of type I interferon-mediated signaling pathway / cGAS/STING signaling pathway / reticulophagy / pattern recognition receptor signaling pathway / cytoplasmic pattern recognition receptor signaling pathway / cellular response to exogenous dsRNA / autophagosome membrane / antiviral innate immune response / positive regulation of macroautophagy / cellular response to organic cyclic compound / autophagosome assembly / 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 / activation of innate immune response / Regulation of innate immune responses to cytosolic DNA / positive regulation of interferon-beta production / endoplasmic reticulum-Golgi intermediate compartment membrane / secretory granule membrane / cytoplasmic vesicle membrane / positive regulation of DNA-binding transcription factor activity / peroxisome / SARS-CoV-1 activates/modulates innate immune responses / positive regulation of protein binding / protein complex oligomerization / regulation of inflammatory response / defense response to virus / RNA polymerase II-specific DNA-binding transcription factor binding / mitochondrial outer membrane / 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 | |||||||||||||||
Biological species | Homo sapiens (human) | |||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.9 Å | |||||||||||||||
Authors | Li J / Canham SM / Zhang X / Bai X / Feng Y | |||||||||||||||
Funding support | United States, 4 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_29282.map.gz | 4.5 MB | EMDB map data format | |
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Header (meta data) | emd-29282-v30.xml emd-29282.xml | 17.8 KB 17.8 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_29282_fsc.xml | 7.7 KB | Display | FSC data file |
Images | emd_29282.png | 100 KB | ||
Filedesc metadata | emd-29282.cif.gz | 6.1 KB | ||
Others | emd_29282_half_map_1.map.gz emd_29282_half_map_2.map.gz | 28.4 MB 28.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-29282 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-29282 | HTTPS FTP |
-Validation report
Summary document | emd_29282_validation.pdf.gz | 731.9 KB | Display | EMDB validaton report |
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Full document | emd_29282_full_validation.pdf.gz | 731.5 KB | Display | |
Data in XML | emd_29282_validation.xml.gz | 13.1 KB | Display | |
Data in CIF | emd_29282_validation.cif.gz | 18.1 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-29282 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-29282 | HTTPS FTP |
-Related structure data
Related structure data | 8flmMC 8flkC C: citing same article (ref.) M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_29282.map.gz / Format: CCP4 / Size: 38.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.08 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #1
File | emd_29282_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_29282_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : STING tetramer
Entire | Name: STING tetramer |
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Components |
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-Supramolecule #1: STING tetramer
Supramolecule | Name: STING tetramer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 Details: STING tetramer, which can further assemblies into larger oligomers, induced by cGAMP, NVS-STG2 and C53 |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 300 KDa |
-Macromolecule #1: Stimulator of interferon genes protein
Macromolecule | Name: Stimulator of interferon genes protein / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 39.553398 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: 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: 4-({[4-(2-tert-butyl-5,5-dimethyl-1,3-dioxan-2-yl)phenyl]methyl}a...
Macromolecule | Name: 4-({[4-(2-tert-butyl-5,5-dimethyl-1,3-dioxan-2-yl)phenyl]methyl}amino)-3-methoxybenzoic acid type: ligand / ID: 2 / Number of copies: 2 / Formula: Y6H |
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Molecular weight | Theoretical: 427.533 Da |
Chemical component information | ChemComp-Y6H: |
-Macromolecule #3: cGAMP
Macromolecule | Name: cGAMP / type: ligand / ID: 3 / Number of copies: 2 / Formula: 1SY |
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Molecular weight | Theoretical: 674.411 Da |
Chemical component information | ChemComp-1SY: |
-Macromolecule #4: 1-[(2-chloro-6-fluorophenyl)methyl]-3,3-dimethyl-2-oxo-N-[(2,4,6-...
Macromolecule | Name: 1-[(2-chloro-6-fluorophenyl)methyl]-3,3-dimethyl-2-oxo-N-[(2,4,6-trifluorophenyl)methyl]-2,3-dihydro-1H-indole-6-carboxamide type: ligand / ID: 4 / Number of copies: 2 / Formula: 9IM |
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Molecular weight | Theoretical: 490.877 Da |
Chemical component information | ChemComp-9IM: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: NITROGEN |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
+Image processing
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: AB INITIO MODEL |
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Output model | PDB-8flm: |