EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Structural basis of anticancer drug recognition and amino acid transport by LAT1.
ジャーナル・号・ページ	Nat Commun, Vol. 16, Issue 1, Page 1635, Year 2025
掲載日	2025年2月14日
著者	Yongchan Lee / Chunhuan Jin / Ryuichi Ohgaki / Minhui Xu / Satoshi Ogasawara / Rangana Warshamanage / Keitaro Yamashita / Garib Murshudov / Osamu Nureki / Takeshi Murata / Yoshikatsu Kanai /
PubMed 要旨	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 ...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.
リンク	Nat Commun / PubMed:39952931 / PubMed Central
手法	EM (単粒子)
解像度	3.58 - 4.12 Å
構造データ	37132 8kdd EMDB-37132, PDB-8kdd: Structure of LAT1-CD98hc-Fab170 in complex with JPH203, consensus map 手法: EM (単粒子) / 解像度: 3.83 Å 37134 8kdf EMDB-37134, PDB-8kdf: Structure of LAT1-CD98hc in complex with JPH203, focused on TMD 手法: EM (単粒子) / 解像度: 3.89 Å 37135 8kdg EMDB-37135, PDB-8kdg: Structure of LAT1-CD98hc-Fab170 in complex with BCH, consensus map 手法: EM (単粒子) / 解像度: 3.68 Å 37136 8kdh EMDB-37136, PDB-8kdh: Structure of LAT1-CD98hc in complex with BCH, focused on TMD 手法: EM (単粒子) / 解像度: 3.78 Å 37137 8kdi EMDB-37137, PDB-8kdi: Structure of apo inward-open LAT1-CD98hc-Fab170 in nanodisc, consensus map 手法: EM (単粒子) / 解像度: 3.58 Å 37138 8kdj EMDB-37138, PDB-8kdj: Structure of apo inward-open LAT1-CD98h in nanodisc, focused on TMD 手法: EM (単粒子) / 解像度: 3.73 Å 37140 8kdn EMDB-37140, PDB-8kdn: Structure of LAT1-CD98hc in complex with L-Phe, focused on TMD 手法: EM (単粒子) / 解像度: 4.12 Å 37141 8kdo EMDB-37141, PDB-8kdo: Structure of LAT1-CD98hc in complex with melphalan, focused on TMD 手法: EM (単粒子) / 解像度: 4.12 Å 37142 8kdp EMDB-37142, PDB-8kdp: Structure of apo outward-open LAT1-CD98h in nanodisc, focused on TMD 手法: EM (単粒子) / 解像度: 4.12 Å
化合物	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose / N-アセチル-β-D-グルコサミン化合物画像なし ChemComp-VRW: Unknown entry ChemComp-CLR: CHOLESTEROL / コレステロ-ル ChemComp-LBN: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / リン脂質YM 化合物画像なし ChemComp-VU0: Unknown entry ChemComp-PHE: PHENYLALANINE / フェニルアラニン化合物画像なし ChemComp-VUC*: Unknown entry
由来	homo sapiens (ヒト) mus musculus (ハツカネズミ)
キーワード	TRANSPORT PROTEIN / Transporter / Amino acid / Complex / Cancer / TRANSPORT PROTEIN/IMMUNE SYSTEM / Glycoprotein / TRANSPORT PROTEIN-IMMUNE SYSTEM complex