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 insights into binding-site access and ligand recognition by human ABCB1.
ジャーナル・号・ページ	EMBO J, Vol. 44, Issue 4, Page 991-991006, Year 2025
掲載日	2025年1月13日
著者	Devanshu Kurre / Phuoc X Dang / Le T M Le / Varun V Gadkari / Amer Alam /
PubMed 要旨	ABCB1 is a broad-spectrum efflux pump central to cellular drug handling and multidrug resistance in humans. However, how it is able to recognize and transport a wide range of diverse substrates ...ABCB1 is a broad-spectrum efflux pump central to cellular drug handling and multidrug resistance in humans. However, how it is able to recognize and transport a wide range of diverse substrates remains poorly understood. Here we present cryo-EM structures of lipid-embedded human ABCB1 in conformationally distinct apo-, substrate-bound, inhibitor-bound, and nucleotide-trapped states at 3.4-3.9 Å resolution, in the absence of stabilizing antibodies or mutations. The substrate-binding site is located within one half of the molecule and, in the apo state, is obstructed by the transmembrane helix (TM) 4. Substrate and inhibitor binding are distinguished by major TM rearrangements and their ligand binding chemistry, with TM4 playing a central role in all conformational transitions. Furthermore, our data identify secondary structure-breaking residues that impart localized TM flexibility and asymmetry between the two transmembrane domains. The resulting structural changes and lipid interactions that are induced by substrate and inhibitor binding can predict substrate-binding profiles and may direct ABCB1 inhibitor design.
リンク	EMBO J / PubMed:39806099 / PubMed Central
手法	EM (単粒子)
解像度	3.4 - 4.7 Å
構造データ	45854 9cr8 EMDB-45854, PDB-9cr8: SapNP reconstituted human ABCB1 手法: EM (単粒子) / 解像度: 3.8 Å 45903 9ctc EMDB-45903, PDB-9ctc: SapNP reconstituted Human ABCB1 in complex with Zosuquidar and ATP/Mg 手法: EM (単粒子) / 解像度: 3.6 Å 45904 9ctf EMDB-45904, PDB-9ctf: SapNP Reconstituted Human ABCB1 bound to Taxol in presence of ATP 手法: EM (単粒子) / 解像度: 3.9 Å 45906 9ctg EMDB-45906, PDB-9ctg: SapNP Reconstituted Human ABCB1 bound to ATP gammaS 手法: EM (単粒子) / 解像度: 3.4 Å EMDB-45931: HUMAN ABCB1 in SapNPs in complex with Taxol 手法: EM (単粒子) / 解像度: 4.7 Å EMDB-45932: HUMAN ABCB1 in SapNPs in complex with Zosuquidar 手法: EM (単粒子) / 解像度: 3.6 Å
化合物	ChemComp-UPL: UNKNOWN BRANCHED FRAGMENT OF PHOSPHOLIPID ChemComp-ATP: ADENOSINE-5'-TRIPHOSPHATE / ATP / ATP, エネルギー貯蔵分子YM ChemComp-ZQU: Zosuquidar / LY-335979 / 抗腫瘍剤YM ChemComp-TA1: TAXOL / パクリタキセル / 薬剤, 化学療法薬YM ChemComp-MG: Unknown entry / マグネシウムジカチオン ChemComp-AGS: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-γ-S / ATP-gamma-S, エネルギー貯蔵分子類似体YM
由来	homo sapiens (ヒト)
キーワード	MEMBRANE PROTEIN / TRANSLOCASE / ABCB1 / P-gp / apo form / nanoparticle / saposin A / MDR1 / p-glycoprotein / pgp / inhibitor bound / saposin / zosuquidar bound / substrate bound / taxol bound / php / ATPgammaS bound / non-hydrolysable nucleotide