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)
| Protein | Definition | Taxonomy |
|---|---|---|
| Stimulator of interferon genes protein | A transmembrane protein 173 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q86WV6] | Homo sapiens (human) |
| Reduced folate transporter | A reduced folate transporter that is encoded in the genome of human. [PRO:DNx, UniProtKB:P41440] | Homo sapiens (human) |
Compounds (10)
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| vadimezan | vadimezan : 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 |
| methotrexate | dicarboxylic 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-deazaaminopterin | 10-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 |
| mangostin | alpha-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 phosphate | cyclic di-AMP : A cyclic purine dinucleotide that is the 3',5'-cyclic dimer of AMP. | adenyl ribonucleotide; cyclic purine dinucleotide | Mycoplasma genitalium metabolite |
| raltitrexed | N-acyl-amino acid | ||
| pemetrexed | pemetrexed 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 acid | cyclic purine dinucleotide; guanyl ribonucleotide | immunomodulator; signalling molecule | |
| cyclic guanosine monophosphate-adenosine monophosphate | c-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 monophosphate | 2'-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 |