CrossRef Open Access 2023 19 sitasi

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

Chiara Brunocilla Lara Console Filomena Rovella Cesare Indiveri

Abstrak

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.

Penulis (4)

C

Chiara Brunocilla

L

Lara Console

F

Filomena Rovella

C

Cesare Indiveri

Format Sitasi

Brunocilla, C., Console, L., Rovella, F., Indiveri, C. (2023). Insights into the Transport Cycle of LAT1 and Interaction with the Inhibitor JPH203. https://doi.org/10.3390/ijms24044042

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Informasi Jurnal
Tahun Terbit
2023
Bahasa
en
Total Sitasi
19×
Sumber Database
CrossRef
DOI
10.3390/ijms24044042
Akses
Open Access ✓