4KSC

Structures of P-glycoprotein reveal its conformational flexibility and an epitope on the nucleotide-binding domain

4KSC の概要

• エントリーDOI: 10.2210/pdb4ksc/pdb
• 関連するPDBエントリー: 4KSB 4KSD 4LSG
• 分子名称: Multidrug resistance protein 1A (1 entity in total)
• 機能のキーワード: transporter, atp binding, membrane, membrane protein, transport protein
• 由来する生物種: Mus musculus (mouse)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 141877.88

構造登録者

Ward, A.,Szewczyk, P.,Grimard, V.,Lee, C.-W.,Martinez, L.,Doshi, R.,Caya, A.,Villaluz, M.,Pardon, E.,Cregger, C.,Swartz, D.J.,Falson, P.,Urbatsch, I.,Govaerts, C.,Steyaert, J.,Chang, G. (登録日: 2013-05-17, 公開日: 2013-07-31, 最終更新日: 2024-02-28)

主引用文献

Ward, A.B.,Szewczyk, P.,Grimard, V.,Lee, C.W.,Martinez, L.,Doshi, R.,Caya, A.,Villaluz, M.,Pardon, E.,Cregger, C.,Swartz, D.J.,Falson, P.G.,Urbatsch, I.L.,Govaerts, C.,Steyaert, J.,Chang, G.
Structures of P-glycoprotein reveal its conformational flexibility and an epitope on the nucleotide-binding domain.
Proc.Natl.Acad.Sci.USA, 110:13386-13391, 2013

PubMed Abstract: P-glycoprotein (P-gp) is one of the best-known mediators of drug efflux-based multidrug resistance in many cancers. This validated therapeutic target is a prototypic, plasma membrane resident ATP-Binding Cassette transporter that pumps xenobiotic compounds out of cells. The large, polyspecific drug-binding pocket of P-gp recognizes a variety of structurally unrelated compounds. The transport of these drugs across the membrane is coincident with changes in the size and shape of this pocket during the course of the transport cycle. Here, we present the crystal structures of three inward-facing conformations of mouse P-gp derived from two different crystal forms. One structure has a nanobody bound to the C-terminal side of the first nucleotide-binding domain. This nanobody strongly inhibits the ATP hydrolysis activity of mouse P-gp by hindering the formation of a dimeric complex between the ATP-binding domains, which is essential for nucleotide hydrolysis. Together, these inward-facing conformational snapshots of P-gp demonstrate a range of flexibility exhibited by this transporter, which is likely an essential feature for the binding and transport of large, diverse substrates. The nanobody-bound structure also reveals a unique epitope on P-gp.

PubMed: 23901103
DOI: 10.1073/pnas.1309275110

実験手法

X-RAY DIFFRACTION (4 Å)