ternary complex formation
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2021 ◽  
Author(s):  
Charu Chaudhry

Proteolysis targeting chimeras (PROTACs), heterobifunctional protein degraders, have emerged as an exciting and transformative technology in chemical biology and drug discovery to degrade disease-causing proteins through co-opting of the ubiquitin-proteosome system (UPS). Here we develop a mechanistic mathematical model for the use of irreversible covalent chemistry in targeted protein degradation (TPD), either to the target protein of interest (POI) or E3 ligase ligand, considering the thermodynamic and kinetic factors governing ternary complex formation, ubiquitination, and degradation through the UPS. We highlight key advantages of covalency to POI and E3 ligase, and the underlying theoretical basis in the TPD reaction framework. We further identify regimes where covalency can serve to overcome weak binary binding affinities and improve kinetics of ternary complex formation and degradation. Our results highlight the enhanced catalytic efficiency of covalent E3 PROTACs and thus their potential to improve the degradation of fast turnover targets.


2021 ◽  
Author(s):  
Anand Divakaran ◽  
Huda Zahid ◽  
Wenwei Lin ◽  
Taosheng Chen ◽  
Dan Harki ◽  
...  

Targeted protein degradation is a powerful induced-proximity tool to control cellular concentrations of native proteins using small molecules. However, the design of selectivity in protein degradation remains challenging. In the case of Bromodomain and Extra-Terminal (BET) family proteins, BRD4 has emerged as the primary therapeutic target over other family members BRD2, 3 and T, but strategies to selectively degrade BRD4 rely on the use of pan-BET inhibitors optimized for BRD4:E3 protein-ubiquitin ligase (E3) ternary complex formation. Here, we report a potent and selective inhibitor for the first bromodomain of BRD4, iBRD4-BD1 (IC50 = 12 nM, 23-6200-fold intra-BET selectivity). We further use this novel inhibitor to develop dBRD4-BD1 that induces selective degradation of BRD4 at a DC50 of 280 nM. The design of BRD4 selectivity up-front enables the study of BRD4 biology in the absence of wider BET-inhibition, simplifies design of future BRD4-selective degraders as new E3 recruiting ligands are discovered, and provides a tool to design additional heterobifunctional BRD4-selective probes.


Author(s):  
Yoselin Jara ◽  
Mary Lorena Araujo ◽  
Waleska Madden ◽  
Vito Lubes ◽  
Lino Hernández

Author(s):  
Anggie Nobrega ◽  
Vanessa R Landaeta ◽  
Rafael Rodriguez-Lugo ◽  
Mary Lorena Araujo ◽  
Waleska Madden ◽  
...  

Author(s):  
Nan Bai ◽  
Sven A. Miller ◽  
Grigorii V. Andrianov ◽  
Max Yates ◽  
Palani Kirubakaran ◽  
...  

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kirsten P. Stone ◽  
Sujoy Ghosh ◽  
Jean Paul Kovalik ◽  
Manda Orgeron ◽  
Desiree Wanders ◽  
...  

AbstractThe initial sensing of dietary methionine restriction (MR) occurs in the liver where it activates an integrated stress response (ISR) that quickly reduces methionine utilization. The ISR program is regulated in part by ATF4, but ATF4’s prototypical upstream regulator, eIF2α, is not acutely activated by MR. Bioinformatic analysis of RNAseq and metabolomics data from liver samples harvested 3 h and 6 h after initiating MR shows that general translation is inhibited at the level of ternary complex formation by an acute 50% reduction of hepatic methionine that limits formation of initiator methionine tRNA. The resulting ISR is induced by selective expression of ATF4 target genes that mediate adaptation to reduced methionine intake and return hepatic methionine to control levels within 4 days of starting the diet. Complementary in vitro experiments in HepG2 cells after knockdown of ATF4, or inhibition of mTOR or Erk1/2 support the conclusion that the early induction of genes by MR is partially dependent on ATF4 and regulated by both mTOR and Erk1/2. Taken together, these data show that initiation of dietary MR induces an mTOR- and Erk1/2-dependent stress response that is linked to ATF4 by the sharp, initial drop in hepatic methionine and resulting repression of translation pre-initiation.


2021 ◽  
Author(s):  
Christian Hartmann ◽  
Eva-Maria Thüring ◽  
Birgitta E. Michels ◽  
Denise Pajonczyk ◽  
Sophia Leußink ◽  
...  

AbstractIntestinal epithelial cells form dense arrays of microvilli at the apical membrane to enhance their functional capacity. Microvilli contain a protocadherin-based intermicrovillar adhesion complex localized at their tips which regulates microvillar length and packaging. Here, we identify a second adhesive complex in microvilli of intestinal epithelial cells. This complex is localized at the basal region of microvilli and consists of the adhesion molecule TMIGD1, the phosphoprotein EBP50 and the F-actin – plasma membrane cross-linking protein ezrin. Ternary complex formation requires unmasking of the EBP50 PDZ domains by ezrin binding and is strongly enhanced upon mutating Ser162 located in PDZ domain 2 of EBP50. Dephosphorylation of EBP50 at S162 is mediated by PP1α, a serine/threonine phosphatase localized at the microvillar base and involved in ezrin phosphocycling. Importantly, the binding of EBP50 to TMIGD1 enhances the dynamic turnover of EBP50 at microvilli in a Ser162 phosphorylation-dependent manner. We identify an adhesive complex at the microvillar base and propose a potential mechanism that regulates microvillar dynamics in enterocytes.


2021 ◽  
Vol 83 (4) ◽  
pp. 934-947
Author(s):  
Asya Drenkova-Tuhtan ◽  
Emily K. Sheeleigh ◽  
Eduard Rott ◽  
Carsten Meyer ◽  
David L. Sedlak

Abstract Magnetic microparticles functionalized with tailored ZnFeZr oxyhydroxide adsorbent were used for the reversible sorption of orthophosphate and recalcitrant organo-phosphonates from wastewater. The loaded particles were harvested magnetically from water, regenerated in an alkaline solution and reused numerous times. The applicability of the technology to treat brackish water reverse osmosis concentrates was tested under controlled synthetic conditions by investigating the influence of typical metals (Ca2+, Pb2+, Cu2+) on the removal of common phosphonates (HEDP, NTMP, EDTMP), and vice versa. When present at equimolar concentrations, metal cations enhanced the adsorption of phosphonates and were co-adsorbed at pH 4.0–4.5 (with removals of 83–93% for Pb2+ and 53–73% for Cu2+), likely through ternary complex formation. In the absence of metals, at pH > pHPZC ∼ 7 (the material point of zero charge), a drop in adsorption efficiency was observed for orthophosphate and all phosphonates. Thus, at pH 7, an increased adsorbent dose (>0.1 g/L) was necessary to remove 1 mg/L NTMP-P in 30 min. The reusability and effluent polishing potential of the ZnFeZr particles was demonstrated in a pilot test with municipal wastewater throughout 55 adsorption/desorption cycles without any drop in performance. Consistent removal of the non-reactive phosphorus species to ultra-low concentrations (<0.05 mg/L Ptot) and complete orthophosphate elimination (<0.005 mg/L PO4-P) was maintained under optimal conditions.


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