Common seafood pollutants inhibit a crucial cellular defense protein.

The organic anion transporters OAT1 (SLC22A6) and OAT3 (SLC22A8) are drug transporters that are expressed in the kidney, with well-established roles in the in vivo transport of drugs and endogenous metabolites. A comparatively unexplored potential function of these drug transporters is their contribution to the in vivo regulation of natural products (NPs) and their effects on endogenous metabolism. This is important for the evaluation of potential NP interactions with other compounds at the transporter site. Here, we have analyzed the NPs present in several well-established databases from Asian (Chinese, Indian Ayurvedic) and other traditions. Loss of OAT1 and OAT3 in murine knockouts caused serum alterations of many NPs, including flavonoids, vitamins, and indoles. OAT1- and OAT3-dependent NPs were largely separable based on a multivariate analysis of chemical properties. Direct binding to the transporter was confirmed using in vitro transport assays and protein binding assays. Our in vivo and in vitro results, considered in the context of previous data, demonstrate that OAT1 and OAT3 play a pivotal role in the handling of non-synthetic small molecule natural products, NP-derived antioxidants, phytochemicals, and nutrients (e.g., pantothenic acid, thiamine). As described by remote sensing and signaling theory, drug transporters help regulate redox states by meditating the movement of endogenous antioxidants and nutrients between organs and organisms. Our results demonstrate how dietary antioxidants and other NPs might feed into these inter-organ and inter-organismal pathways.

Aim: This work aims to contribute toward development of preventive measures for the control of monkeypox (mpox) virus disease through computational design of a multiepitope vaccine. Methods: To acc... Plain language summary The recent outbreak of mpox virus presents a significant public health threat with no treatment available. While the use of smallpox vaccines remains the current strategy for... Graphical abstract Graphical abstract illustrating the workflow of a multiepitope vaccine design against mpox virus. (A) Prediction of the transmembrane protein with identification of the extracell...

P-glycoprotein (Pgp) detoxifies cells by exporting hundreds of chemically unrelated toxins but has been implicated in multidrug resistance in the treatment of cancers. Substrate promiscuity is a hallmark of Pgp activity, thus a structural description of polyspecific drug-binding is important for the rational design of anticancer drugs and MDR inhibitors. The x-ray structure of apo-Pgp at 3.8 Å reveals an internal cavity of ∼6,000 Å3 with a 30 Å separation of the two nucleotide binding domains (NBD). Two additional Pgp structures with cyclic peptide inhibitors demonstrate distinct drug binding sites in the internal cavity capable of stereo-selectivity that is based on hydrophobic and aromatic interactions. Apo- and drug-bound Pgp structures have portals open to the cytoplasm and the inner leaflet of the lipid bilayer for drug entry. The inward-facing conformation represents an initial stage of the transport cycle that is competent for drug binding. We will present our latest findings on P-glycoprotein and present strategy on obtaining other conformations, extending the diffraction resolution, and new co-crystal structures with inhibitors/drugs.

Persistent pollutants in the ocean impact the safety of seafood. Many emerging and legacy persistent organic pollutants (POPs) have been disposed into the world's oceans, exemplified by the recent discovery of large amounts of the halogenated pesticide dichlorodiphenyltrichloroethane (DDT) waste in the waters of Southern California. The biological mechanisms governing persistence and trophic transfer of marine pollutants into seafood species remain incompletely understood. Xenobiotic transporters, such as P-glycoprotein (P-gp), are present in all organisms and prevent the accumulation of toxic chemicals. Our previous work has demonstrated that halogenated marine pollutants can act as inhibitors of human and murine P-gp transporters by interacting with their binding site and impeding transport. Using cryo-EM, we determined the molecular interactions of DDT with P-glycoprotein from yellowfin tuna (Thunnus albacares). The results reveal that the conformation of the transporter samples multiple degrees of widening in the absence of substrate. We also show that DDT binds in a singular, wide inward-facing conformation that could inhibit the transport cycle. This transporter inhibition may contribute to the bioaccumulation of DDT in tuna. This study highlights the capacity of persistent organic pollutants to act at multiple points in the food chain to inhibit this critical transport mechanism.