Page last updated: 2024-10-24

2',3'-cyclic GMP-AMP binding

Definition

Target type: molecularfunction

Binding to 2',3' cyclic GMP-AMP (cGAMP) nucleotide, a cyclic purine dinucleotide that consists of AMP and GMP units cyclized via 2',5' and 3',5' linkages. [GOC:dph, PMID:23258412, PMID:23910378]

2',3'-cyclic GMP-AMP (cGAMP) is a cyclic dinucleotide second messenger that plays a critical role in innate immune signaling. It is synthesized by the enzyme cGAS upon recognition of cytosolic DNA from viruses or bacteria. cGAMP functions as an activator of the STING protein, a key signaling molecule in the innate immune response.

The molecular function of cGAMP binding to STING involves several key steps:

1. **Binding to the STING dimer:** cGAMP binds to the dimeric STING protein through two distinct sites. One site is located in the transmembrane domain, while the other is located in the cytosolic domain. This binding event initiates conformational changes within the STING protein.
2. **Induction of STING oligomerization:** Upon binding to cGAMP, STING molecules undergo oligomerization, forming higher-order structures. This oligomerization is essential for activating downstream signaling pathways.
3. **Recruitment of TBK1:** The oligomerized STING complex recruits the protein kinase TBK1. TBK1 is a key player in the activation of the interferon regulatory factor 3 (IRF3) pathway.
4. **Activation of IRF3:** TBK1 phosphorylates and activates IRF3, a transcription factor responsible for the expression of type I interferons (IFNs).

The binding of cGAMP to STING triggers a cascade of events that ultimately lead to the production of type I IFNs, which are essential for the antiviral and antibacterial immune responses. The specific molecular interactions between cGAMP and STING, including the precise conformational changes and the roles of different amino acid residues, are being actively studied to gain a deeper understanding of this critical signaling pathway.
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Proteins (2)

ProteinDefinitionTaxonomy
Stimulator of interferon genes proteinA transmembrane protein 173 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q86WV6]Homo sapiens (human)
Reduced folate transporterA reduced folate transporter that is encoded in the genome of human. [PRO:DNx, UniProtKB:P41440]Homo sapiens (human)

Compounds (10)

CompoundDefinitionClassesRoles
vadimezanvadimezan : A monocarboxylic acid that is acetic acid in which one of the methyl hydrogens is replaced by a 5,6-dimethyl-9-oxoxanthen-4-yl group.monocarboxylic acid;
xanthones
antineoplastic agent
methotrexatedicarboxylic acid;
monocarboxylic acid amide;
pteridines
abortifacient;
antimetabolite;
antineoplastic agent;
antirheumatic drug;
dermatologic drug;
DNA synthesis inhibitor;
EC 1.5.1.3 (dihydrofolate reductase) inhibitor;
immunosuppressive agent
10-propargyl-10-deazaaminopterin10-propargyl-10-deazaaminopterin: structure in first source

pralatrexate : A pteridine that is the N-4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]benzoyl derivative of L-glutamic acid. Used for treatment of Peripheral T-Cell Lymphoma, an aggressive form of non-Hodgkins lymphoma.
N-acyl-L-glutamic acid;
pteridines;
terminal acetylenic compound
antimetabolite;
antineoplastic agent;
EC 1.5.1.3 (dihydrofolate reductase) inhibitor
mangostinalpha-mangostin : A member of the class of xanthones that is 9H-xanthene substituted by hydroxy group at positions 1, 3 and 6, a methoxy group at position 7, an oxo group at position 9 and prenyl groups at positions 2 and 8. Isolated from the stems of Cratoxylum cochinchinense, it exhibits antioxidant, antimicrobial and antitumour activities.

mangostin: xanthone from rind of Garcinia mangostana Linn. fruit
aromatic ether;
phenols;
xanthones
antimicrobial agent;
antineoplastic agent;
antioxidant;
plant metabolite
cyclic diadenosine phosphatecyclic di-AMP : A cyclic purine dinucleotide that is the 3',5'-cyclic dimer of AMP.adenyl ribonucleotide;
cyclic purine dinucleotide
Mycoplasma genitalium metabolite
raltitrexedN-acyl-amino acid
pemetrexedpemetrexed disodium : An organic sodium salt that is the disodium salt of N-{4-[2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L-glutamic acid. Inhibits thymidylate synthase (TS), 421 dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT).N-acyl-L-glutamic acid;
pyrrolopyrimidine
antimetabolite;
antineoplastic agent;
EC 1.5.1.3 (dihydrofolate reductase) inhibitor;
EC 2.1.1.45 (thymidylate synthase) inhibitor;
EC 2.1.2.2 (phosphoribosylglycinamide formyltransferase) inhibitor
bis(3',5')-cyclic diguanylic acidcyclic purine dinucleotide;
guanyl ribonucleotide
immunomodulator;
signalling molecule
cyclic guanosine monophosphate-adenosine monophosphatec-GMP-AMP : A cyclic purine dinucleotide that consists of AMP and GMP units cyclised via 3',5'-linkages.adenyl ribonucleotide;
cyclic purine dinucleotide;
guanyl ribonucleotide
cyclic guanosine monophosphate-adenosine monophosphate2'-3'-cGAMP : A cyclic purine dinucleotide that consists of AMP and GMP units cyclised via 3',5'- and 2',5'-linkages respectively.adenyl ribonucleotide;
cyclic purine dinucleotide;
guanyl ribonucleotide