PDBsum entry 4ksc

Membrane protein, transport protein

PDB id: 4ksc

Contents

Protein chain

1182 a.a.

PDB id:

4ksc

Name:

Membrane protein, transport protein

Title:

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

Structure:

Multidrug resistance protein 1a. Chain: a. Synonym: atp-binding cassette sub-family b member 1a, mdr1a, multidrug resistance protein 3, p-glycoprotein 3. Engineered: yes

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: abcb1a, abcb4, mdr1a, mdr3, pgy-3, pgy3. Expressed in: komagataella pastoris. Expression_system_taxid: 4922

Resolution:

4.00Å R-factor: 0.317 R-free: 0.338

Authors:

A.Ward,P.Szewczyk,V.Grimard,C.-W.Lee,L.Martinez,R.Doshi,A.Caya, M.Villaluz,E.Pardon,C.Cregger,D.J.Swartz,P.Falson,I.Urbatsch, C.Govaerts,J.Steyaert,G.Chang

Key ref:

A.B.Ward et al. (2013). Structures of P-glycoprotein reveal its conformational flexibility and an epitope on the nucleotide-binding domain. Proc Natl Acad Sci U S A, 110, 13386-13391. PubMed id: 23901103 DOI: 10.1073/pnas.1309275110

Date:

17-May-13 Release date: 31-Jul-13

Protein chain

P21447  (MDR1A_MOUSE) -  ATP-dependent translocase ABCB1 from Mus musculus

Seq: 1276 a.a.

Struc: 1182 a.a.

Enzyme reactions

• Enzyme class 1: E.C.7.6.2.1 - P-type phospholipid transporter.
• Reaction: ATP + H2O + phospholipidSide 1 = ADP + phosphate + phospholipidSide 2
• Enzyme class 2: E.C.7.6.2.2 - ABC-type xenobiotic transporter.
• Reaction: ATP + H2O + xenobioticSide 1 = ADP + phosphate + xenobioticSide 2

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1073/pnas.1309275110

Proc Natl Acad Sci U S A 110:13386-13391 (2013)

PubMed id: 23901103

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

A.B.Ward, P.Szewczyk, V.Grimard, C.W.Lee, L.Martinez, R.Doshi, A.Caya, M.Villaluz, E.Pardon, C.Cregger, D.J.Swartz, P.G.Falson, I.L.Urbatsch, C.Govaerts, J.Steyaert, G.Chang.

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.