8PY4

ABCG2 in complex with ko143 and 5D3 Fab

8PY4 の概要

• エントリーDOI: 10.2210/pdb8py4/pdb
• EMDBエントリー: 18003 18016
• 分子名称: 5d3(fab) heavy chain variable domain, 5D3(Fab) light chain variable domain, Broad substrate specificity ATP-binding cassette transporter ABCG2, ... (7 entities in total)
• 機能のキーワード: multidrug transporter, transport protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 247583.66

構造登録者

Yu, Q.,Kowal, J.,Tajkhorshid, E.,Altmann, K.H.,Locher, K.P. (登録日: 2023-07-25, 公開日: 2024-11-06, 最終更新日: 2024-11-27)

主引用文献

Yu, Q.,Dehghani-Ghahnaviyeh, S.,Rasouli, A.,Sadurni, A.,Kowal, J.,Bang-Soerensen, R.,Wen, P.C.,Tinzl-Zechner, M.,Irobalieva, R.N.,Ni, D.,Stahlberg, H.,Altmann, K.H.,Tajkhorshid, E.,Locher, K.P.
Modulation of ABCG2 Transporter Activity by Ko143 Derivatives.
Acs Chem.Biol., 19:2304-2313, 2024

PubMed Abstract: ABCG2 is a multidrug transporter that protects tissues from xenobiotics, affects drug pharmacokinetics, and contributes to multidrug resistance of cancer cells. Here, we present tetracyclic fumitremorgin C analog Ko143 derivatives, evaluate their modulation of purified ABCG2, and report four high-resolution cryo-EM structures and computational analyses to elucidate their interactions with ABCG2. We found that Ko143 derivatives that are based on a ring-opened scaffold no longer inhibit ABCG2-mediated transport activity. In contrast, closed-ring, tetracyclic analogs were highly potent inhibitors. Strikingly, the least potent of these compounds, MZ82, bound deeper into the central ABCG2 cavity than the other inhibitors and it led to partial closure of the transmembrane domains and increased flexibility of the nucleotide-binding domains. Minor structural modifications can thus convert a potent inhibitor into a compound that induces conformational changes in ABCG2 similar to those observed during binding of a substrate. Molecular dynamics simulations and free energy binding calculations further supported the correlation between reduced potency and distinct binding pose of the compounds. We introduce the highly potent inhibitor AZ99 that may exhibit improved stability.

PubMed: 39445888
DOI: 10.1021/acschembio.4c00353

実験手法

ELECTRON MICROSCOPY (3 Å)