Periodic Reporting for period 4 - TRECEPTORS (Transport and Receptor Mechanisms of Human Solute Carriers)
Reporting period: 2023-01-01 to 2023-09-30
Human solute carriers are integral membrane proteins that serve multiple multiple and essential functions in the body. They transport solutes and ions across the membrane allowing cells to exchange nutrients, metabolites, and signalling molecules with the external media. They are also important receptors of cellular and pathogenic proteins. Solute carriers are involved in numerous pathologic conditions, and constitute emergent drug targets in metabolic, neurological and infectious diseases, as well as human cancer.
Our goal is to understand the function and pharmacology of important solute carriers at the molecular and structural levels. We also aim at developing novel molecules targeting solute carriers with therapeutic potential for the above-mentioned diseases.
The results of this project have expanded our knowledge on how solute carriers achieve their transport and receptor functions, as well as the molecular interlinks between the two. During the execution of the project, we developed novel molecules that helped us achieving our goals and that importantly, hold potential to aid developing novel therapeutic tools to treat human viral infection and cancer.
Our goal is to understand the function and pharmacology of important solute carriers at the molecular and structural levels. We also aim at developing novel molecules targeting solute carriers with therapeutic potential for the above-mentioned diseases.
The results of this project have expanded our knowledge on how solute carriers achieve their transport and receptor functions, as well as the molecular interlinks between the two. During the execution of the project, we developed novel molecules that helped us achieving our goals and that importantly, hold potential to aid developing novel therapeutic tools to treat human viral infection and cancer.
The main results and outcomes associated to TRECEPTORS are:
-The elucidation of the transport and hepatitis-B-virus receptor mechanisms of a central protein in the liver. We have recently reported the structures and mechanisms of a central protein expressed in the liver and known as NTCP. This carrier is the main uptake route of bile acid molecules into the liver from the blood, and the cell-entry receptor of human hepatitis B and D viruses (Goutam et al., Nature 2022).
-The discovery of the 2 transport and retroviral-receptor mechanisms of an essential omega-3 fatty acid human carrier. The Major-Facilitator Superfamily transporter MFSD2A has two important functions in the human body: it is the main uptake route of essential omega-3 fatty acids into the brain, and the cellular receptor of the membrane fusogenic protein syncytin-2 that mediates cell fusion during placenta development. We recently reported structures of MFSD2A-SYNC2 complexes that shed light on the mechanisms underlying the two functions (Martinez-Molledo et al., Nat. Struct. Mol. Biol. 2022).
-The discovery of the receptor-recognition and antiviral mechanisms of human placental proteins, namely sycytin-1 and suppressyn. Human syncytin-1 and supressyn are cellular proteins of retroviral origin that catalyze and regulate cell-cell fusion events to establish the maternal-fetal interface in the placenta. In cell culture, they restrict infections from members of the largest interference group of vertebrate retroviruses, including simian viruses with zoonotic potential, and are regarded as host-immunity factors expressed during development. We have determined the cryo-EM structures of syncytin-1 and Suppresyn complexes with their common cellular receptor, the amino acid transporter ASCT2 (Khare et al., Nat. Struct. Mol. Biol. accepted).
-Patent applications on novel molecules with therapeutic potential. The above-mentioned human carriers, NTCP and MFSD2A are emergent drug targets to prevent viral infections and to facilitate therapeutic-drug delivery into the brain, respectively. We have generated novel allosteric modulators of both proteins and filed patent applications to initiate technology transfer of these molecules to industry.
-Seven structures and cryo-EM maps have been deposited in public databases.
-The elucidation of the transport and hepatitis-B-virus receptor mechanisms of a central protein in the liver. We have recently reported the structures and mechanisms of a central protein expressed in the liver and known as NTCP. This carrier is the main uptake route of bile acid molecules into the liver from the blood, and the cell-entry receptor of human hepatitis B and D viruses (Goutam et al., Nature 2022).
-The discovery of the 2 transport and retroviral-receptor mechanisms of an essential omega-3 fatty acid human carrier. The Major-Facilitator Superfamily transporter MFSD2A has two important functions in the human body: it is the main uptake route of essential omega-3 fatty acids into the brain, and the cellular receptor of the membrane fusogenic protein syncytin-2 that mediates cell fusion during placenta development. We recently reported structures of MFSD2A-SYNC2 complexes that shed light on the mechanisms underlying the two functions (Martinez-Molledo et al., Nat. Struct. Mol. Biol. 2022).
-The discovery of the receptor-recognition and antiviral mechanisms of human placental proteins, namely sycytin-1 and suppressyn. Human syncytin-1 and supressyn are cellular proteins of retroviral origin that catalyze and regulate cell-cell fusion events to establish the maternal-fetal interface in the placenta. In cell culture, they restrict infections from members of the largest interference group of vertebrate retroviruses, including simian viruses with zoonotic potential, and are regarded as host-immunity factors expressed during development. We have determined the cryo-EM structures of syncytin-1 and Suppresyn complexes with their common cellular receptor, the amino acid transporter ASCT2 (Khare et al., Nat. Struct. Mol. Biol. accepted).
-Patent applications on novel molecules with therapeutic potential. The above-mentioned human carriers, NTCP and MFSD2A are emergent drug targets to prevent viral infections and to facilitate therapeutic-drug delivery into the brain, respectively. We have generated novel allosteric modulators of both proteins and filed patent applications to initiate technology transfer of these molecules to industry.
-Seven structures and cryo-EM maps have been deposited in public databases.
We have advanced the knowledge on the viral and cellular receptor functions of human solute carriers.