Biology subjects

Walton, W. G.

Publications and source records attributed to Walton, W. G..

2 recordsLinked to original sources

bioRxiv2021

The plant immune receptors NRG1.1 and ADR1 are calcium influx channels

Plant nucleotide-binding leucine-rich repeat receptors (NLRs) regulate immunity and cell death. RPW8 domain-containing "helper" NLRs (RNLs) are required by many "sensor" NLRs. Our crystal structure of the RNL N REQUIREMENT GENE 1.1 (NRG1.1) N-terminal signaling domain resembled that of the resting state plant resistosome-forming HOPZ-ACTIVATED RESISTANCE 1 (ZAR1) and the animal MIXED-LINEAGE KINASE-LIKE (MLKL) cation channel. Active NRG1.1 oligomerized, was enriched in plasma membrane puncta and conferred cytoplasmic Ca2+ influx in plant and human HeLa cells. NRG1.1-dependent Ca2+ influx and cell death were sensitive to Ca2+ channel blockers. Ca2+ influx and cell death mediated by NRG1.1 and ACTIVATED DISEASE RESISTANCE 1 (ADR1), another RNL, required conserved negatively charged N-terminal residues. Thus, RNLs apparently form influx channels to directly regulate cytoplasmic [Ca2+] and consequent cell death. One Sentence SummaryA specific class of plant immune receptors function as calcium-permeable channels upon activation to induce cell death.

plant biology↗

bioRxiv2019

Targeting the Pregnane X Receptor Using Microbial Metabolite Mimicry

The human pregnane X receptor (PXR), a master regulator of drug metabolism, has important roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off-target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows to exploit previously unexplored parts of chemical space. Here we report functionalized indole-derivatives as first-in-class non-cytotoxic PXR agonists, as a proof-of-concept for microbial metabolite mimicry. The lead compound, FKK6, binds directly to PXR protein in solution, induces PXR specific target gene expression in, cells, human organoids, and mice. FKK6 significantly represses pro-inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to mine underexploited regions of chemical space.

biochemistry↗