5VDO

Human cyclic GMP-AMP synthase (cGAS) in complex with 2',2'-cGAMP

Summary for 5VDO

• Entry DOI: 10.2210/pdb5vdo/pdb
• Related: 5VDP 5VDQ 5VDR 5VDS 5VDT 5VDU 5VDV 5VDW
• Descriptor: Cyclic GMP-AMP synthase, ZINC ION, 2-amino-9-[(1R,3R,6R,8R,9R,11S,14R,16R,17R,18R)-16-(6-amino-9H-purin-9-yl)-3,11,17,18-tetrahydroxy-3,11-dioxido-2,4,7,10,12,15-hexaoxa-3,11-diphosphatricyclo[12.2.1.1~6,9~]octadec-8-yl]-1,9-dihydro-6H-purin-6-one, ... (4 entities in total)
• Functional Keywords: transferase, sting, cgamp
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm, cytosol . Note=(Microbial infection) Upon infection with virulent M: Q8N884
• Total number of polymer chains: 2
• Total formula weight: 86551.84

Authors

Byrnes, L.J.,Hall, J.D. (deposition date: 2017-04-03, release date: 2017-09-27, Last modification date: 2023-10-04)

Primary citation

Hall, J.,Ralph, E.C.,Shanker, S.,Wang, H.,Byrnes, L.J.,Horst, R.,Wong, J.,Brault, A.,Dumlao, D.,Smith, J.F.,Dakin, L.A.,Schmitt, D.C.,Trujillo, J.,Vincent, F.,Griffor, M.,Aulabaugh, A.E.
The catalytic mechanism of cyclic GMP-AMP synthase (cGAS) and implications for innate immunity and inhibition.
Protein Sci., 26:2367-2380, 2017

PubMed Abstract: Cyclic GMP-AMP synthase (cGAS) is activated by ds-DNA binding to produce the secondary messenger 2',3'-cGAMP. cGAS is an important control point in the innate immune response; dysregulation of the cGAS pathway is linked to autoimmune diseases while targeted stimulation may be of benefit in immunoncology. We report here the structure of cGAS with dinucleotides and small molecule inhibitors, and kinetic studies of the cGAS mechanism. Our structural work supports the understanding of how ds-DNA activates cGAS, suggesting a site for small molecule binders that may cause cGAS activation at physiological ATP concentrations, and an apparent hotspot for inhibitor binding. Mechanistic studies of cGAS provide the first kinetic constants for 2',3'-cGAMP formation, and interestingly, describe a catalytic mechanism where 2',3'-cGAMP may be a minor product of cGAS compared with linear nucleotides.

PubMed: 28940468
DOI: 10.1002/pro.3304

Experimental method

X-RAY DIFFRACTION (3.218 Å)