4KSC: Structures Of P-glycoprotein Reveal Its Conformational Flexibility And An Epitope On The Nucleotide-binding Domain

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.
PDB ID: 4KSCDownload
MMDB ID: 112279
PDB Deposition Date: 2013/5/17
Updated in MMDB: 2015/09
Experimental Method:
x-ray diffraction
Resolution: 4  Å
Similar Structures:
Biological Unit for 4KSC: monomeric; determined by author and by software (PISA)
Molecular Components in 4KSC
Label Count Molecule
Protein (1 molecule)
Multidrug Resistance Protein 1A(Gene symbol: Abcb1a)
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB