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Article

Insights into the Transport Cycle of LAT1 and Interaction with the Inhibitor JPH203

1
Department DiBEST (Biologia, Ecologia, Scienze Della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria, Via Bucci 4C, 87036 Arcavacata di Rende, Italy
2
CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), Via Amendola 122/O, 70126 Bari, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2023, 24(4), 4042; https://doi.org/10.3390/ijms24044042
Submission received: 30 December 2022 / Revised: 8 February 2023 / Accepted: 15 February 2023 / Published: 17 February 2023
(This article belongs to the Special Issue Early-Stage Drug Discovery: Advances and Challenges)

Abstract

The large Amino Acid Transporter 1 (LAT1) is an interesting target in drug discovery since this transporter is overexpressed in several human cancers. Furthermore, due to its location in the blood-brain barrier (BBB), LAT1 is interesting for delivering pro-drugs to the brain. In this work, we focused on defining the transport cycle of LAT1 using an in silico approach. So far, studies of the interaction of LAT1 with substrates and inhibitors have not considered that the transporter must undergo at least four different conformations to complete the transport cycle. We built outward-open and inward-occluded conformations of LAT1 using an optimized homology modelling procedure. We used these 3D models and the cryo-EM structures in outward-occluded and inward-open conformations to define the substrate/protein interaction during the transport cycle. We found that the binding scores for the substrate depend on the conformation, with the occluded states as the crucial steps affecting the substrate affinity. Finally, we analyzed the interaction of JPH203, a high-affinity inhibitor of LAT1. The results indicate that conformational states must be considered for in silico analyses and early-stage drug discovery. The two built models, together with the available cryo-EM 3D structures, provide important information on the LAT1 transport cycle, which could be used to speed up the identification of potential inhibitors through in silico screening.
Keywords: conformational changes; in silico analysis; SLC7A5; transport cycle; transport proteins conformational changes; in silico analysis; SLC7A5; transport cycle; transport proteins

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MDPI and ACS Style

Brunocilla, C.; Console, L.; Rovella, F.; Indiveri, C. Insights into the Transport Cycle of LAT1 and Interaction with the Inhibitor JPH203. Int. J. Mol. Sci. 2023, 24, 4042. https://doi.org/10.3390/ijms24044042

AMA Style

Brunocilla C, Console L, Rovella F, Indiveri C. Insights into the Transport Cycle of LAT1 and Interaction with the Inhibitor JPH203. International Journal of Molecular Sciences. 2023; 24(4):4042. https://doi.org/10.3390/ijms24044042

Chicago/Turabian Style

Brunocilla, Chiara, Lara Console, Filomena Rovella, and Cesare Indiveri. 2023. "Insights into the Transport Cycle of LAT1 and Interaction with the Inhibitor JPH203" International Journal of Molecular Sciences 24, no. 4: 4042. https://doi.org/10.3390/ijms24044042

APA Style

Brunocilla, C., Console, L., Rovella, F., & Indiveri, C. (2023). Insights into the Transport Cycle of LAT1 and Interaction with the Inhibitor JPH203. International Journal of Molecular Sciences, 24(4), 4042. https://doi.org/10.3390/ijms24044042

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