Human multidrug resistance protein 5 (hMRP5) effluxes anticancer and antivirus drugs, driving multidrug resistance. To uncover the mechanism of hMRP5, we determine six distinct cryo-EM structures, revealing an autoinhibitory N-terminal peptide that must dissociate to permit subsequent substrate recruitment. Guided by these molecular insights, we design an inhibitory peptide that could block substrate entry into the transport pathway.
View Article and Find Full Text PDFHuman multidrug resistance protein 4 (hMRP4, also known as ABCC4), with a representative topology of the MRP subfamily, translocates various substrates across the membrane and contributes to the development of multidrug resistance. However, the underlying transport mechanism of hMRP4 remains unclear due to a lack of high-resolution structures. Here, we use cryogenic electron microscopy (cryo-EM) to resolve its near-atomic structures in the apo inward-open and the ATP-bound outward-open states.
View Article and Find Full Text PDFDysregulation of polyamine homeostasis strongly associates with human diseases. ATP13A2, which is mutated in juvenile-onset Parkinson's disease and autosomal recessive spastic paraplegia 78, is a transporter with a critical role in balancing the polyamine concentration between the lysosome and the cytosol. Here, to better understand human ATP13A2-mediated polyamine transport, we use single-particle cryo-electron microscopy to solve high-resolution structures of human ATP13A2 in six intermediate states, including the putative E2 structure for the P5 subfamily of the P-type ATPases.
View Article and Find Full Text PDFAdhesion G protein-coupled receptors are elusive in terms of their structural information and ligands. Here, we solved the cryogenic-electron microscopy (cryo-EM) structure of apo-ADGRG2, an essential membrane receptor for maintaining male fertility, in complex with a G trimer. Whereas the formations of two kinks were determinants of the active state, identification of a potential ligand-binding pocket in ADGRG2 facilitated the screening and identification of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate and deoxycorticosterone as potential ligands of ADGRG2.
View Article and Find Full Text PDFFish Shellfish Immunol
November 2020
Peroxiredoxins (Prxs) are crucial antioxidant proteins that protect against biotic and abiotic stresses in many organisms, ranging from bacteria to mammals. In the present work, a novel 2-Cys Peroxiredoxin gene (PmPrxn), which contains a 153 bp 5'-terminal untranslated region (5'-UTR), a 636 bp open reading frame encoding a protein with 211 amino acids, and an 898 bp 3'-UTR, was successfully identified and characterized in the black tiger shrimp, Penaeus monodon. Tissue-specific expression analysis revealed that the PmPrxn mRNA was ubiquitously expressed and was comparatively highly expressed in the hepatopancreas.
View Article and Find Full Text PDFAs a unique atypical 2-Cys Peroxiredoxin (Prx) of the Prx-like superfamily, Peroxiredoxin5 (Prx5) possesses special properties, such as its enzymatic mechanism, wide subcellular distribution and high affinity for peroxides and peroxynitrite. Prx5 plays a crucial role in oxidative stress, immune responses, cell apoptosis, proliferation, differentiation, intracellular signaling, the modulation of gene expression, ecdysis, etc. In this paper, we obtained a full-length Prx5 cDNA sequence (designated PmPrx5) from black tiger shrimp (P.
View Article and Find Full Text PDFPeroxiredoxins (Prxs) are ubiquitous, multifunctional and evolutionarily conserved enzymes that can protect cells from oxidative damage caused by ROS and play a vital role in immune responses. Here, a full-length Prx1 cDNA sequence (PmPrx1) was isolated from Penaeus monodon. The PmPrx1 cDNA was 951 base pairs (bp), encoding 198 amino acid polypeptides.
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