Abstract:
:The spliceosome mediates precursor mRNA splicing in eukaryotes, including the model organism Saccharomyces cerevisiae (yeast). Despite decades of study, no chemical inhibitors of yeast splicing in vivo are available. We have developed a system to efficiently inhibit splicing and block proliferation in living yeast cells using compounds that target the human spliceosome protein SF3B1. Potent inhibition is observed in yeast expressing a chimeric protein containing portions of human SF3B1. However, only a single point mutation in the yeast homolog of SF3B1 is needed for selective inhibition of splicing by pladienolide B, herboxidiene, or meayamycin in liquid culture. Mutations that enable inhibition also improve splicing of branch sites containing mismatches between the intron and small nuclear RNA-suggesting a link between inhibitor sensitivity and usage of weak branch sites in humans. This approach provides powerful new tools for manipulating splicing in live yeast and studies of spliceosome inhibitors.
journal_name
Cell Chem Bioljournal_title
Cell chemical biologyauthors
Hansen SR,Nikolai BJ,Spreacker PJ,Carrocci TJ,Hoskins AAdoi
10.1016/j.chembiol.2018.11.008subject
Has Abstractpub_date
2019-03-21 00:00:00pages
443-448.e3issue
3eissn
2451-9456issn
2451-9448pii
S2451-9456(18)30430-6journal_volume
26pub_type
杂志文章abstract::Numerous near-infrared (NIR) fluorescent proteins (FPs) were recently engineered from bacterial photoreceptors but lack of their systematic comparison makes researcher's choice rather difficult. Here we evaluated side-by-side several modern NIR FPs, such as blue-shifted smURFP and miRFP670, and red-shifted mIFP and mi...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2017.05.018
更新日期:2017-06-22 00:00:00
abstract::Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a promising class of targeted cancer drugs, but their individual target profiles beyond the PARP family, which could result in differential clinical use or toxicity, are unknown. Using an unbiased, mass spectrometry-based chemical proteomics approach, we genera...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2016.10.011
更新日期:2016-12-22 00:00:00
abstract::The engineered ascorbate peroxidase (APEX) is a powerful tool for the proximity-dependent labeling of proteins and RNAs in live cells. Although widely use in mammalian cells, APEX applications in microorganisms have been hampered by the poor labeling efficiency of its biotin-phenol (BP) substrate. In this study, we so...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2020.05.006
更新日期:2020-07-16 00:00:00
abstract::Tumor suppressor genes represent a major class of oncogenic drivers. However, direct targeting of loss-of-function tumor suppressors remains challenging. To address this gap, we explored a variant-directed chemical biology approach to reverse the lost function of tumor suppressors using SMAD4 as an example. SMAD4, a c...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2020.11.010
更新日期:2020-12-04 00:00:00
abstract::Advances in understanding the role and molecular mechanisms underlying immune surveillance and control of (pre)malignancies is revolutionizing clinical practice in the treatment of cancer. Presently, multiple biologic drugs targeting the immune checkpoint proteins PD(L)1 or CTLA4 have been approved and/or are in advan...
journal_title:Cell chemical biology
pub_type: 杂志文章,评审
doi:10.1016/j.chembiol.2017.08.019
更新日期:2017-09-21 00:00:00
abstract::The natural product cepafungin I was recently reported to be one of the most potent covalent inhibitors of the 20S proteasome core particle through a series of in vitro activity assays. Here, we report a short chemoenzymatic total synthesis of cepafungin I featuring the use of a regioselective enzymatic oxidation to p...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2020.07.012
更新日期:2020-10-15 00:00:00
abstract::Owing to their structural flexibility, most serpins inhibit the cognate proteases in a fast and specific manner and also are susceptible to pathogenic misfolding. In this issue of Cell Chemical Biology, Madsen et al. (2016) report on the selection and characterization of an RNA aptamer that stabilizes α1-antichymotryp...
journal_title:Cell chemical biology
pub_type: 评论,杂志文章
doi:10.1016/j.chembiol.2016.06.002
更新日期:2016-06-23 00:00:00
abstract::G-quadruplexes are specialized secondary structures in nucleic acids that possess significant conformational polymorphisms. The precise G-quadruplex conformations in vivo and their relevance to biological functions remain controversial and unclear, especially for telomeric G-quadruplexes. Here, we report a novel singl...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2016.08.013
更新日期:2016-10-20 00:00:00
abstract::Energy coupling factor (ECF) transporters are responsible for the uptake of essential scarce nutrients in prokaryotes. This ATP-binding cassette transporter family comprises two subgroups that share a common architecture forming a tripartite membrane protein complex consisting of a translocation component and ATP hydr...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2016.06.008
更新日期:2016-07-21 00:00:00
abstract::Contrary to the classic model of protein kinase A (PKA) residing outside of the nucleus, we identify a nuclear signaling complex that consists of AKAP95, PKA, and PDE4D5 and show that it forms a functional cyclic AMP (cAMP) signaling microdomain. Locally generated cAMP can accumulate within the vicinity of this comple...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2019.03.003
更新日期:2019-06-20 00:00:00
abstract::In this issue of Cell Chemical Biology, Diaz et al. (2017) report a strategy to achieve temporal, spatial, and stoichiometric control over the protein kinase cAbl in living cells. They achieve this by splitting cAbl into two inactive fragments that form an active kinase upon small molecule addition, potentially provid...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2017.10.004
更新日期:2017-10-19 00:00:00
abstract::The glycan ligands recognized by Siglecs, influenza viruses, and galectins, as well as many plant lectins, are not well defined. To explore their binding to asparagine (Asn)-linked N-glycans, we synthesized a library of isomeric multiantennary N-glycans that vary in terminal non-reducing sialic acid, galactose, and N-...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2019.01.002
更新日期:2019-04-18 00:00:00
abstract::A better in vivo understanding of lignin formation within plant cell walls will contribute to improving the valorization of plant-derived biomass. Although bioorthogonal chemistry provides a promising platform to study the lignification process, methodologies that simultaneously detect multiple chemical reporters in l...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2017.02.009
更新日期:2017-03-16 00:00:00
abstract::Increased telomerase activity is associated with malignancy and poor prognosis in human cancer, but the development of targeted agents has not yet provided clinical benefit. Here we report that, instead of targeting the telomerase enzyme directly, small molecules that bind to the G-hairpin of the hTERT G-quadruplex-fo...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2019.04.009
更新日期:2019-08-15 00:00:00
abstract::In this issue of Cell Chemical Biology, Radlinski et al. (2019) identify Pseudomonas-derived rhamnolipids that potentiate aminoglycoside antibiotics in the eradication of antibiotic-tolerant bacterial phenotypes. Microbial physiological and mechanistic studies indicate that rhamnolipids permeabilize S. aureus membrane...
journal_title:Cell chemical biology
pub_type: 评论,杂志文章
doi:10.1016/j.chembiol.2019.09.015
更新日期:2019-10-17 00:00:00
abstract::Small-molecule targeted recruitment of nucleases to RNA is a powerful method to affect RNA biology. Inforna, a sequence-based design approach to target RNA, enables the design of small molecules that bind to and cleave RNA in a selective and substoichiometric manner. Here, we investigate the ability of RNA-targeted de...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2019.04.008
更新日期:2019-08-15 00:00:00
abstract::A protein-fragment complementation assay (PCA) for detecting and localizing intracellular protein-protein interactions (PPIs) was built by bisection of miniSOG, a fluorescent flavoprotein derived from the light, oxygen, voltage (LOV)-2 domain of Arabidopsis phototropin. When brought together by interacting proteins, t...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2019.07.007
更新日期:2019-10-17 00:00:00
abstract::Dengue virus infects more than 300 million people annually, yet there is no widely protective vaccine or drugs against the virus. Efforts to develop antivirals against classical targets such as the viral protease and polymerase have not yielded drugs that have advanced to the clinic. Here, we show that the allosteric ...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2016.03.010
更新日期:2016-04-21 00:00:00
abstract::Lethal small molecules are useful probes to discover and characterize novel cell death pathways and biochemical mechanisms. Here we report that the synthetic oxime-containing small molecule caspase-independent lethal 56 (CIL56) induces an unconventional form of nonapoptotic cell death distinct from necroptosis, ferrop...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2019.09.014
更新日期:2019-12-19 00:00:00
abstract::The cysteine prodrug N-acetyl cysteine (NAC) is widely used as a pharmacological antioxidant and cytoprotectant. It has been reported to lower endogenous oxidant levels and to protect cells against a wide range of pro-oxidative insults. As NAC itself is a poor scavenger of oxidants, the molecular mechanisms behind the...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2018.01.011
更新日期:2018-04-19 00:00:00
abstract::USP7 is a deubiquitinating enzyme that plays a pivotal role in multiple oncogenic pathways and therefore is a desirable target for new anti-cancer therapies. However, the lack of structural information about the USP7-inhibitor interactions has been a critical gap in the development of potent inhibitors. USP7 is unique...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2017.09.004
更新日期:2017-12-21 00:00:00
abstract::The promise of phenotypic screening resides in its track record of novel biology and first-in-class therapies. However, challenges stemming from major differences between target-based and phenotypic screening do exist. These challenges prompted us to rethink the critical stage of hit triage and validation on the road ...
journal_title:Cell chemical biology
pub_type: 杂志文章,评审
doi:10.1016/j.chembiol.2020.08.009
更新日期:2020-11-19 00:00:00
abstract::Electron microscopy (EM) remains the primary method for imaging cellular and tissue ultrastructure, although simultaneous localization of multiple specific molecules continues to be a challenge for EM. We present a method for obtaining multicolor EM views of multiple subcellular components. The method uses sequential,...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2016.10.006
更新日期:2016-11-17 00:00:00
abstract::New opportunities to advance small-molecule kinase ligands that downregulate their cognate target binding proteins are discussed. Rationally designed heterobifunctional kinase degraders are compared with ATP site ligands that were serendipitously found to cause kinase downregulation. These approaches could be particul...
journal_title:Cell chemical biology
pub_type: 杂志文章,评审
doi:10.1016/j.chembiol.2017.10.011
更新日期:2018-01-18 00:00:00
abstract::In this issue of Cell Chemical Biology, Shah et al. (2019) report an in vitro, high-throughput assay that predicts the ability of compounds to suppress peroxidation of phospholipids. This approach provides a way to design and optimize targeted antioxidants that suppress specific oxidative event in cells, potentially o...
journal_title:Cell chemical biology
pub_type: 评论,杂志文章
doi:10.1016/j.chembiol.2019.11.003
更新日期:2019-11-21 00:00:00
abstract::The rapid emergence of extensively drug-resistant A. baumannii has posed a major threat to global public health, emphasizing the desperate need for novel therapeutic strategies. We report the development of a highly efficient genome-engineering platform in A. baumannii by coupling a Cas9 nuclease-mediated genome cleav...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2019.09.003
更新日期:2019-12-19 00:00:00
abstract::In this issue of Cell Chemical Biology, Harvey et al. (2020) identify 4E14, a sulfhydryl-containing N-acetyltryptophan analog that selectively disrupts binding to the previously undruggable anti-apoptotic BCL2 paralog BFL1, and elucidate a BFL1 conformational change that facilitates 4E14 interaction. These results pro...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2020.05.014
更新日期:2020-06-18 00:00:00
abstract::Interfacial inhibitors exert their biological effects through co-association with two macromolecules. The pateamine A (PatA) class of molecules function by stabilizing eukaryotic initiation factor (eIF) 4A RNA helicase onto RNA, resulting in translation initiation inhibition. Here, we present the crystal structure of ...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2020.12.006
更新日期:2021-01-05 00:00:00
abstract::Identification and validation of the targets of bioactive small molecules identified in cell-based screening is challenging and often meets with failure, calling for the development of new methodology. We demonstrate that a combination of chemical proteomics with in silico target prediction employing the SPiDER method...
journal_title:Cell chemical biology
pub_type: 杂志文章
doi:10.1016/j.chembiol.2018.05.016
更新日期:2018-09-20 00:00:00
abstract::In this issue of Cell Chemical Biology,De Cesare et al. (2018) report the development of a high-throughput assay that measures E2/E3 enzyme activity by MALDI-TOF mass spectrometry and apply this to screen for small molecule E3 inhibitors. This assay potentially accelerates the drug discovery for the ubiquitin ligation...
journal_title:Cell chemical biology
pub_type: 评论,杂志文章
doi:10.1016/j.chembiol.2018.09.002
更新日期:2018-09-20 00:00:00