Cryo-EM Structures of Apo and DDT-Bound P-Glycoprotein in Yellowfin Tuna

Abstract

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.