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	Mechanism of substrate transport and inhibition of the human LAT1-4F2hc amino acid transporter.
ジャーナル・号・ページ	Cell Discov, Vol. 7, Issue 1, Page 16, Year 2021
掲載日	2021年3月23日
著者	Renhong Yan / Yaning Li / Jennifer Müller / Yuanyuan Zhang / Simon Singer / Lu Xia / Xinyue Zhong / Jürg Gertsch / Karl-Heinz Altmann / Qiang Zhou /
PubMed 要旨	LAT1 (SLC7A5) is one of the representative light chain proteins of heteromeric amino acid transporters, forming a heterodimer with its heavy chain partner 4F2hc (SLC3A2). LAT1 is overexpressed in ...LAT1 (SLC7A5) is one of the representative light chain proteins of heteromeric amino acid transporters, forming a heterodimer with its heavy chain partner 4F2hc (SLC3A2). LAT1 is overexpressed in many types of tumors and mediates the transfer of drugs and hormones across the blood-brain barrier. Thus, LAT1 is considered as a drug target for cancer treatment and may be exploited for drug delivery into the brain. Here, we synthesized three potent inhibitors of human LAT1, which inhibit transport of leucine with IC values between 100 and 250 nM, and solved the cryo-EM structures of the corresponding LAT1-4F2hc complexes with these inhibitors bound at resolution of up to 2.7 or 2.8 Å. The protein assumes an outward-facing occluded conformation, with the inhibitors bound in the classical substrate binding pocket, but with their tails wedged between the substrate binding site and TM10 of LAT1. We also solved the complex structure of LAT1-4F2hc with 3,5-diiodo-L-tyrosine (Diiodo-Tyr) at 3.4 Å overall resolution, which revealed a different inhibition mechanism and might represent an intermediate conformation between the outward-facing occluded state mentioned above and the outward-open state. To our knowledge, this is the first time that the outward-facing conformation is revealed for the HAT family. Our results unveil more important insights into the working mechanisms of HATs and provide a structural basis for future drug design.
リンク	Cell Discov / PubMed:33758168 / PubMed Central
手法	EM (単粒子)
解像度	2.7 - 3.4 Å
構造データ	30835 7dsk EMDB-30835: cryo EM map of the LAT1-4F2hc bound with JX-075 PDB-7dsk: Overall structure of the LAT1-4F2hc bound with JX-075 手法: EM (単粒子) / 解像度: 2.9 Å EMDB-30836: cryo EM map of the LAT1-4F2hc bound with JX-075, focused refined on transmembrane region 手法: EM (単粒子) / 解像度: 2.7 Å 30837 7dsl EMDB-30837: cryo EM map of the LAT1-4F2hc bound with JX-078 PDB-7dsl: Overall structure of the LAT1-4F2hc bound with JX-078 手法: EM (単粒子) / 解像度: 2.9 Å EMDB-30838: cryo EM map of the LAT1-4F2hc bound with JX-078, focused refined on transmembrane region 手法: EM (単粒子) / 解像度: 2.7 Å 30839 7dsn EMDB-30839: cryo EM map of the LAT1-4F2hc bound with JX-119 PDB-7dsn: Overall structure of the LAT1-4F2hc bound with JX-119 手法: EM (単粒子) / 解像度: 3.1 Å EMDB-30840: cryo EM map of the LAT1-4F2hc bound with JX-119, focused refined on transmembrane region 手法: EM (単粒子) / 解像度: 2.8 Å 30841 7dsq EMDB-30841: cryo EM map of the LAT1-4F2hc bound with 3,5-diiodo-L-tyrosine PDB-7dsq: Overall structure of the LAT1-4F2hc bound with 3,5-diiodo-L-tyrosine 手法: EM (単粒子) / 解像度: 3.4 Å EMDB-30842: cryo EM map of the LAT1-4F2hc bound with 3,5-diiodo-L-tyrosine, focused refined on transmembrane region 手法: EM (単粒子) / 解像度: 3.3 Å
化合物	ChemComp-3PH: 1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE / ジステアロイルホスファチジン酸 ChemComp-HNX: (2~{S})-2-azanyl-7-(naphthalen-1-ylmethoxy)-3,4-dihydro-1~{H}-naphthalene-2-carboxylic acid ChemComp-Y01: CHOLESTEROL HEMISUCCINATE / コレステリルヘミスクシナ-ト ChemComp-HOH: WATER ChemComp-HO0: (2~{S})-2-azanyl-7-[(2-phenylphenyl)methoxy]-3,4-dihydro-1~{H}-naphthalene-2-carboxylic acid ChemComp-HO9: (2~{S})-2-azanyl-7-[[2-(1,3-benzoxazol-2-yl)phenyl]methoxy]-3,4-dihydro-1~{H}-naphthalene-2-carboxylic acid ChemComp-TYI: 3,5-DIIODOTYROSINE / 3,5-ジヨ-ド-L-チロシン / ホルモン*YM
由来	homo sapiens (ヒト)
キーワード	MEMBRANE PROTEIN / LAT1-4F2hc