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	Transport mechanism and structural pharmacology of human urate transporter URAT1.
ジャーナル・号・ページ	Cell Res, Vol. 34, Issue 11, Page 776-787, Year 2024
掲載日	2024年9月9日
著者	Yaxin Dai / Chia-Hsueh Lee /
PubMed 要旨	Urate is an endogenous product of purine metabolism in the liver. High urate levels in the blood lead to gout, a very common and painful inflammatory arthritis. Excreted urate is reabsorbed in the ...Urate is an endogenous product of purine metabolism in the liver. High urate levels in the blood lead to gout, a very common and painful inflammatory arthritis. Excreted urate is reabsorbed in the kidney mainly by URAT1 antiporter, a key target for anti-gout drugs. To uncover the mechanisms of urate transport and drug inhibition, we determined cryo-EM structures of human URAT1 with urate, counter anion pyrazinoate, or anti-gout drugs of different chemotypes - lesinurad, verinurad, and dotinurad. We captured the outward-to-inward transition of URAT1 during urate uptake, revealing that urate binds in a phenylalanine-rich pocket and engages with key gating residues to drive the transport cycle. In contrast to the single binding site for urate, pyrazinoate interacts with three distinct, functionally relevant sites within URAT1, a mechanism that has not yet been observed in other anion antiporters. In addition, we found that while all three drugs compete with substrates and halt the transport cycle, verinurad and dotinurad further hijack gating residues to achieve high potency. These insights advance our understanding of organic anion transport and provide a foundation for designing improved gout therapeutics.
リンク	Cell Res / PubMed:39245778 / PubMed Central
手法	EM (単粒子)
解像度	2.7 - 3.7 Å
構造データ	44077 9b1f EMDB-44077, PDB-9b1f: Human urate transporter 1 URAT1 in apo state 手法: EM (単粒子) / 解像度: 2.9 Å 44078 9b1g EMDB-44078, PDB-9b1g: Human urate transporter 1 URAT1 in complex with dotinurad 手法: EM (単粒子) / 解像度: 2.7 Å 44079 9b1h EMDB-44079, PDB-9b1h: Human urate transporter 1 URAT1 in complex with lesinurad 手法: EM (単粒子) / 解像度: 2.9 Å 44080 9b1i EMDB-44080, PDB-9b1i: Human urate transporter 1 URAT1 in complex with verinurad 手法: EM (単粒子) / 解像度: 3.7 Å 44081 9b1j EMDB-44081, PDB-9b1j: Urate bound human URAT1 in the inward-facing state 手法: EM (単粒子) / 解像度: 3.0 Å 44082 9b1k EMDB-44082, PDB-9b1k: Urate bound human URAT1 in the occluded state 手法: EM (単粒子) / 解像度: 3.3 Å 44083 9b1l EMDB-44083, PDB-9b1l: Urate bound human URAT1 in the outward-facing state. 手法: EM (単粒子) / 解像度: 3.1 Å 44084 9b1m EMDB-44084, PDB-9b1m: Pyrazinoate bound human URAT1 in the inward-facing state (site1) 手法: EM (単粒子) / 解像度: 3.0 Å 44085 9b1n EMDB-44085, PDB-9b1n: Pyrazinoate bound human URAT1 in the inward-facing state (site2) 手法: EM (単粒子) / 解像度: 3.1 Å 44086 9b1o EMDB-44086, PDB-9b1o: Pyrazinoate bound human URAT1 in the inward-facing state (site3) 手法: EM (単粒子) / 解像度: 3.1 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 PDB-1aik: HIV GP41 CORE STRUCTURE PDB-1ail: N-TERMINAL FRAGMENT OF NS1 PROTEIN FROM INFLUENZA A VIRUS PDB-1aij: PHOTOSYNTHETIC REACTION CENTER FROM RHODOBACTER SPHAEROIDES IN THE CHARGE-NEUTRAL DQAQB STATE ChemComp-URC: URIC ACID / 尿酸 ChemComp-PO4: PHOSPHATE ION / ホスファ-ト ChemComp-VGL: PYRAZINE-2-CARBOXYLIC ACID / 2-ピラジンカルボン酸
由来	homo sapiens (ヒト)
キーワード	MEMBRANE PROTEIN / SLC transporter / SLC22A family / uric acid / inward facing / SLC22 family / inward open / inhibitor / outward facing