4ksd

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

spinqualitylabelsall models 4ksd, resolution 4.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ksd is a 2 chain structure with sequence from Camelus glama and Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Related: 4ksb, 4ksc, 4lsg Gene: Abcb1a, Abcb4, Mdr1a, Mdr3, Pgy-3, Pgy3 (LK3 transgenic mice), r2 (Camelus glama) Activity: Xenobiotic-transporting ATPase, with EC number 3.6.3.44 Resources: FirstGlance, OCA, RCSB, PDBsum Function [MDR1A_MOUSE] Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells. Publication Abstract from PubMed 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. Structures of P-glycoprotein reveal its conformational flexibility and an epitope on the nucleotide-binding domain.,Ward AB, Szewczyk P, Grimard V, Lee CW, Martinez L, Doshi R, Caya A, Villaluz M, Pardon E, Cregger C, Swartz DJ, Falson PG, Urbatsch IL, Govaerts C, Steyaert J, Chang G Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13386-91. doi:, 10.1073/pnas.1309275110. Epub 2013 Jul 30. PMID:23901103 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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