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Structure paper

TitleStructural basis of anticancer drug recognition and amino acid transport by LAT1.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 1635, Year 2025
Publish dateFeb 14, 2025
AuthorsYongchan Lee / Chunhuan Jin / Ryuichi Ohgaki / Minhui Xu / Satoshi Ogasawara / Rangana Warshamanage / Keitaro Yamashita / Garib Murshudov / Osamu Nureki / Takeshi Murata / Yoshikatsu Kanai /
PubMed AbstractLAT1 (SLC7A5) transports large neutral amino acids and plays pivotal roles in cancer proliferation, immune response and drug delivery. Despite recent advances in structural understanding of LAT1, how ...LAT1 (SLC7A5) transports large neutral amino acids and plays pivotal roles in cancer proliferation, immune response and drug delivery. Despite recent advances in structural understanding of LAT1, how it discriminates substrates and inhibitors including the clinically relevant drugs remains elusive. Here we report six structures of LAT1 across three conformations with bound ligands, elucidating its substrate transport and inhibitory mechanisms. JPH203 (also known as nanvuranlat or KYT-0353), an anticancer drug in clinical trials, traps LAT1 in an outward-facing state with a U-shaped conformer, with its amino-phenylbenzoxazol moiety pushing against transmembrane helix 3 (TM3) and bending TM10. Physiological substrates like ʟ-Phe lack such effects, whereas melphalan poses steric hindrance, explaining its inhibitory activity. The "classical" system L inhibitor BCH induces an occluded state critical for transport, confirming its substrate-like behavior. These findings provide a structural basis for substrate recognition and inhibition of LAT1, guiding future drug design.
External linksNat Commun / PubMed:39952931 / PubMed Central
MethodsEM (single particle)
Resolution3.58 - 4.12 Å
Structure data

37132

8kdd

EMDB-37132, PDB-8kdd:
Structure of LAT1-CD98hc-Fab170 in complex with JPH203, consensus map
Method: EM (single particle) / Resolution: 3.83 Å

37134

8kdf

EMDB-37134, PDB-8kdf:
Structure of LAT1-CD98hc in complex with JPH203, focused on TMD
Method: EM (single particle) / Resolution: 3.89 Å

37135

8kdg

EMDB-37135, PDB-8kdg:
Structure of LAT1-CD98hc-Fab170 in complex with BCH, consensus map
Method: EM (single particle) / Resolution: 3.68 Å

37136

8kdh

EMDB-37136, PDB-8kdh:
Structure of LAT1-CD98hc in complex with BCH, focused on TMD
Method: EM (single particle) / Resolution: 3.78 Å

37137

8kdi

EMDB-37137, PDB-8kdi:
Structure of apo inward-open LAT1-CD98hc-Fab170 in nanodisc, consensus map
Method: EM (single particle) / Resolution: 3.58 Å

37138

8kdj

EMDB-37138, PDB-8kdj:
Structure of apo inward-open LAT1-CD98h in nanodisc, focused on TMD
Method: EM (single particle) / Resolution: 3.73 Å

37140

8kdn

EMDB-37140, PDB-8kdn:
Structure of LAT1-CD98hc in complex with L-Phe, focused on TMD
Method: EM (single particle) / Resolution: 4.12 Å

37141

8kdo

EMDB-37141, PDB-8kdo:
Structure of LAT1-CD98hc in complex with melphalan, focused on TMD
Method: EM (single particle) / Resolution: 4.12 Å

37142

8kdp

EMDB-37142, PDB-8kdp:
Structure of apo outward-open LAT1-CD98h in nanodisc, focused on TMD
Method: EM (single particle) / Resolution: 4.12 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose


ChemComp, No image

ChemComp-VRW:
Unknown entry

ChemComp-CLR:
CHOLESTEROL

ChemComp-LBN:
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / phospholipid*YM


ChemComp, No image

ChemComp-VU0:
Unknown entry

ChemComp-PHE:
PHENYLALANINE


ChemComp, No image

ChemComp-VUC:
Unknown entry

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsTRANSPORT PROTEIN / Transporter / Amino acid / Complex / Cancer / TRANSPORT PROTEIN/IMMUNE SYSTEM / Glycoprotein / TRANSPORT PROTEIN-IMMUNE SYSTEM complex

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