Biology subjects

Ben Shoshan-Galeczki, Y.

Publications and source records attributed to Ben Shoshan-Galeczki, Y..

4 recordsLinked to original sources

bioRxiv2026

Leveraging AI and structural proteomics for rational design of a KAT6A degrader

While targeted protein degraders such as PROTACs are a clinically proven therapeutic strategy, the discovery of novel degraders remains hampered by trial-and-error process. To address this challenge, we developed the AIMS platform, which combines structural proteomics with AI models for rational PROTAC design. AIMS is an end-to-end toolkit for PROTAC optimization, encompassing structure solving using proteomics and AI, prediction of ADME and degradation properties, and prospective ranking of compound design ideas. Altogether, this integrated platform successfully enabled the multi-parameter optimization of a potent and bioavailable in vivo validated KAT6A degrader, establishing a versatile framework for PROTAC development across various targets. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=71 SRC="FIGDIR/small/727609v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@13596d0org.highwire.dtl.DTLVardef@140500eorg.highwire.dtl.DTLVardef@147e585org.highwire.dtl.DTLVardef@12dbdfe_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2023

T1R3 subunit of the sweet taste receptor is activated by D2O in transmembrane domain-dependent manner

Deuterium oxide (D2O) is a water molecule in which both hydrogens are replaced by the heavier and rare isotope deuterium. We have previously shown that D2O has distinct sweet taste, which is mediated by the T1R2/T1R3 sweet taste receptor. Here we explore the effect of heavy water on T1R2 and T1R3 subunits. We show that D2O activates T1R3 transfected HEK293T cells similarly to T1R2/T1R3 transfected cells. The response to glucose dissolved in D2O is higher than to glucose dissolved in water. Mutations of Phenylalanine at position 7305.40 in the transmembrane domain of T1R3 to Alanine, Leucine or Tyrosine, impair or diminish activation by D2O, suggesting a critical role for T1R3 TMD domain in relaying the heavy water signal.

molecular biology↗

bioRxiv2020

Sweet chirality: the taste of L and D glucose stereoisomers

Chirality plays a key role in biomolecular recognition. Typically, a change in chirality will dramatically affect ligand-receptor binding. However, both O_SCPLOWDC_SCPLOW-glucose and its enantiomer O_SCPLOWLC_SCPLOW-glucose elicit sweet taste in humans. We show that O_SCPLOWLC_SCPLOW- and O_SCPLOWDC_SCPLOW-glucose are perceived as similarly sweet by humans, and that in cell-based functional assays, both enantiomers activate the human sweet taste receptor TAS1R2/TAS1R3. We hypothesize that both O_SCPLOWLC_SCPLOW- and O_SCPLOWDC_SCPLOW-glucose occupy the orthosteric binding site in the VFT domain of TAS1R2. Using induced-fit docking to a homology model of this domain, we identify two subpockets in this binding site. The model suggests that glucose molecules can bind in either of these subpockets, which overlap with the predicted positions of monosaccharide units of sucrose. One subpocket is close to the hinge between the two lobes, and overlaps with aspartame and neotame site, the second subpocket overlaps with that described for sweetness enhancers. These findings suggest a framework for rational design of sweeteners combinations.

biochemistry↗

bioRxiv2020

Sweet taste of heavy water

Hydrogen to deuterium isotopic substitution has only a minor effect on physical and chemical properties of water and, as such, is not supposed to influence its neutral taste. Here we conclusively demonstrate that humans are, nevertheless, able to distinguish D2O from H2O by taste. Indeed, highly purified heavy water has a distinctly sweeter taste than same-purity normal water and adds to perceived sweetness of sweeteners. In contrast, mice do not prefer D2O over H2O, indicating that they are not likely to perceive heavy water as sweet. HEK 293T cells transfected with the TAS1R2/TAS1R3 heterodimer and chimeric G-proteins are activated by D2O but not by H2O. Lactisole, which is a known sweetness inhibitor acting via the TAS1R3 monomer of the TAS1R2/TAS1R3, suppresses the sweetness of D2O in human sensory tests, as well as the calcium release elicited by D2O in sweet taste receptor-expressing cells. The present multifaceted experimental study, complemented by homology modelling and molecular dynamics simulations, resolves a long-standing controversy about the taste of heavy water, shows that its sweet taste is mediated by the human TAS1R2/TAS1R3 taste receptor, and opens way to future studies of the detailed mechanism of action. One sentence summaryHeavy water elicits sweet taste for humans via the TAS1R2/TAS1R3 taste receptor.

biochemistry↗