Science Concentrates PROTEIN STRUCTURE
STING structure probed cryo-electron microscopy, or cryo-EM, to Despite its painful-sounding name, the get their structural snapshots of STING. stimulator of interferon genes protein, They observed how human and chicken known as STING, is something you want STING proteins arrange themselves in to have around. When active, STING cell membranes when inactive and how helps ramp up production of inthe chicken STING changes flammatory proteins called when activated. The interferons and cytokines, team imaged the chicken jump-starting a part of STING protein bound to the immune system. a protein called TBK1, to STING was originally which active STING binds identified for its role as part of the process of in antiviral immunity, ramping up the immune but multiple companies system. The scientists also want to find ways to activate explored how a separate STING to sic immune cells pathway without TBK1 can on tumors. At the Universtart the cell’s internal cleanup sity of Texas Southwestern operation, called autophagy. Medical Center, researchers In another study, the team have used structural biology investigated how STING to reveal more about how changes shape when it is STING turns on and how activated by a cyclic dinuthe protein activates a celcleotide known as cGAMP. lular tidy-up (Nature 2019, Structure of full-length STING is a dimer of two DOI: 10.1038/s41586-019chicken STING (yellow protein subunits. When 1000-2, 10.1038/s41586and green) bound to inactive, the parts of the 019-1006-9, and s41586cGAMP (purple) subunits that sit outside 019-0998-5). The images of the membrane wrap around each other. these membrane-bound proteins provide When cGAMP binds, the two subunits scientists with new information to guide straighten up so that each takes hold of the development of molecules to target one side of the dinucleotide. This change STING. makes the dimer more compact, allowing Zhijian Chen and coworkers used
the dimers to stack up, side by side, in the membrane. That side-by-side structure is the same as one reported in a recent preprint from Lingyin Li’s group at Stanford University, which proposes mechanisms for STING activation, inhibition, and hyperactivation (bioRxiv 2019, DOI: 10.1101/552166). Working on human STING, Li’s team also showed that another STING activator, c-di-GMP, has a different effect on the protein’s conformation and partially blocks cGAMP’s ability to turn on STING. Li says she thinks the two groups’ work complements each other. They are, she adds, “big news for STING drug discovery because we now know how cGAMP activates STING and not all STING agonists are created equal.” Li says the data from Chen’s team provide structural explanations for some previous biochemical data on STING. Andrea Ablasser of the Global Health Institute at the Swiss Federal Institute of Technology, Lausanne (EPFL), points out that there are still many unanswered questions about STING, including how the cell regulates both the protein’s movements and the autophagy pathway that Chen’s team identified. However, she says, the high-resolution cryo-EM data provided by Chen’s team will be useful for drug-discovery programs.—LAURA
HOWES
GENOMICS
Possible biomarkers for preterm birth identified Complications of preterm birth—a live birth occurring before 37 weeks of gestation—are a leading cause of death and health problems in children. The genetic and environmental factors that underlie preterm birth are poorly understood. A team led by Leroy Hood of the Institute for Systems Biology and John E. Niederhuber of the Inova Translational Medicine Institute now reports a genomic study that identifies potential biomarkers for preterm birth (Proc. Natl. Acad. Sci. U.S.A. 2019, DOI: 10.1073/pnas.1716314116). The researchers performed whole-genome DNA sequencing, RNA sequenc-
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C&EN | CEN.ACS.ORG | MARCH 11, 2019
ing, and DNA methylation analysis on 791 family trios (mother, father, and child), including 270 preterm births and 521 control families. When they treated all the preterm births as a single group, they couldn’t identify any significant genetic differences. But when they divided the preterm birth group into different clinical subgroups, they were able to identify significant genomic variations. Most significantly, they identified 72 candidate biomarker genes for very early preterm birth—occurring before 28 weeks of gestation. Those genes are involved in growth signaling and inflam-
mation- and immunity-related pathways. Mikko Hallman, a preterm-birth expert at the University of Oulu, says, “This approach likely opens new avenues towards accurate diagnosis of the pregnancies at risk and will eventually lead to the discovery of potential new approaches for prevention.” There’s still work to be done. “Because there are such a variety of clinical risk factors and alterations at the level of the placenta, it will take larger study populations to have enough numbers in every possible subgroup,” Niederhuber says.—CELIA ARNAUD
C R E D I T: NAT UR E
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Work could help drug companies design ways to activate STING to attack cancer
