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Zhang, Z.-C.

Publications and source records attributed to Zhang, Z.-C..

2 recordsLinked to original sources

Microcystins are critical for the toxic Microcystis to survive long-term nitrogen starvation

Toxic cyanobacterial blooms have expanded and intensified on a global scale, but the physiological role of microcystins during bloom development is not fully resolved. Here, we show that microcystin production can increase the survival and resuscitation rate of Microcystis after long-term nitrogen starvation. Our results showed that microcystin production could enable toxic Microcystis to accumulate more carbon reserves under nitrogen limitation, which is critical to support the survival of cells under stressful conditions. Further analysis showed that genes involved in microcystin synthesis were significantly upregulated at the initial phase of recovery, which could help toxic Microcystis to strengthen glycogen catabolism and fuel recovery. The close genetic traits between Microcystis strains suggest the strategies observed here might be highly conserved. Our findings imply how toxic Microcystis establish a competitive advantage over non-toxic species and provide new insight into the seasonal dynamic of the Microcystis population in natural environment. IMPORTANCEMicrocystins are the most abundant cyanotoxins released during harmful algal blooms. While the factors controlling microcystin production have been widely studied, the function of these toxic secondary metabolites under changing environments remains poorly understood. Here we proved that microcystins are critical to toxic Microcystis to maintaining carbon metabolism under long-term nitrogen starvation and subsequent recovery. Compared to the non-toxic strains, microcystin-producing Microcystis exhibit a higher viability and resuscitation rate after prolonged nitrogen starvation, which is consistent with the dominance of these species at the early stage of cyanobacterial blooms. Our findings shed light on the genetic traits that drive population succession during bloom development, which is important for the modeling and prediction of harmful cyanobacterial blooms.

microbiology↗

Structural basis of peptidomimetic agonism revealed by small molecule GLP-1R agonists Boc5 and WB4-24

Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective in treating type 2 diabetes and obesity with proven cardiovascular benefits. However, most of them are peptides and require subcutaneous injection except for orally available semaglutide. Boc5 was identified as the first orthosteric non-peptidic agonist of GLP-1R that mimics a broad spectrum of bioactivities of GLP-1 in vitro and in vivo. Here, we report the cryo-electron microscopy structures of Boc5 and its analog WB4-24 in complex with the human GLP-1R and Gs protein. Bound to the extracellular domain, extracellular loop 2, and transmembrane (TM) helices 1, 2, 3 and 7, one arm of both compounds inserted deeply into the bottom of the orthosteric binding pocket that is usually accessible by peptidic agonists, thereby partially overlapping with the residues A8-D15 in GLP-1. The other three arms, meanwhile, extended to the TM1-TM7, TM1-TM2, and TM2-TM3 clefts showing an interaction feature substantially similar to a previously known small molecule agonist LY3502970. Such a unique binding mode creates a distinct conformation that confers both peptidomimetic agonism and biased signaling induced by non-peptidic modulators at GLP-1R. Further, the conformational difference between Boc5 and WB4-24, two closed related compounds, provides a structural framework for fine tuning of pharmacological efficacy in the development of future small molecule therapeutics targeting GLP-1R. SignificanceGLP-1R agonists are efficacious in the treatment of type 2 diabetes and obesity. While most clinically used agents require subcutaneous injection, Boc5, as the first orthosteric non-peptidic agonist of GLP-1R, suffers from poor oral bioavailability that hinders its therapeutic development. The cryo-electron microscopy structures of Boc5 and its closely related analog WB4-24 presented here reveal a previously unknown binding pocket located deeper in the transmembrane domain for non-peptidic GLP-1R agonists. Molecular interaction with this site may facilitate a broad spectrum of in vivo agonistic activities, in addition to that with the upper helical bundles presumably responsible for biased signaling. These findings deepen our understanding of peptidomimetic agonism at GLP-1R and may help design better drug leads against this important target.

molecular biology↗