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

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 focuse...

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Detalles Bibliográficos
Autores principales: Brunocilla, Chiara, Console, Lara, Rovella, Filomena, Indiveri, Cesare
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9965313/
https://www.ncbi.nlm.nih.gov/pubmed/36835453
http://dx.doi.org/10.3390/ijms24044042
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author Brunocilla, Chiara
Console, Lara
Rovella, Filomena
Indiveri, Cesare
author_facet Brunocilla, Chiara
Console, Lara
Rovella, Filomena
Indiveri, Cesare
author_sort Brunocilla, Chiara
collection PubMed
description 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.
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spelling pubmed-99653132023-02-26 Insights into the Transport Cycle of LAT1 and Interaction with the Inhibitor JPH203 Brunocilla, Chiara Console, Lara Rovella, Filomena Indiveri, Cesare Int J Mol Sci Article 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. MDPI 2023-02-17 /pmc/articles/PMC9965313/ /pubmed/36835453 http://dx.doi.org/10.3390/ijms24044042 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Brunocilla, Chiara
Console, Lara
Rovella, Filomena
Indiveri, Cesare
Insights into the Transport Cycle of LAT1 and Interaction with the Inhibitor JPH203
title Insights into the Transport Cycle of LAT1 and Interaction with the Inhibitor JPH203
title_full Insights into the Transport Cycle of LAT1 and Interaction with the Inhibitor JPH203
title_fullStr Insights into the Transport Cycle of LAT1 and Interaction with the Inhibitor JPH203
title_full_unstemmed Insights into the Transport Cycle of LAT1 and Interaction with the Inhibitor JPH203
title_short Insights into the Transport Cycle of LAT1 and Interaction with the Inhibitor JPH203
title_sort insights into the transport cycle of lat1 and interaction with the inhibitor jph203
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9965313/
https://www.ncbi.nlm.nih.gov/pubmed/36835453
http://dx.doi.org/10.3390/ijms24044042
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