PDBsum entry 7a6c

Transport protein

PDB id: 7a6c

Contents

Protein chains

1164 a.a.

214 a.a.

218 a.a.

Ligands

R0Z ×2

CLR ×10

PDB id:

7a6c

Name:

Transport protein

Title:

Nanodisc reconstituted human abcb1 in complex with mrk16 fab and elacridar

Structure:

Multidrug resistance protein 1. Chain: a. Synonym: atp-binding cassette sub-family b member 1,p-glycoprotein 1. Engineered: yes. If kappa light chain. Chain: b. Engineered: yes. Mrk16 fab-fragment heavy chain. Chain: c.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: abcb1, mdr1, pgy1. Expressed in: homo sapiens. Expression_system_taxid: 9606. Mus musculus. Mouse. Organism_taxid: 10090.

Authors:

K.Nosol,K.P.Locher

Key ref:

K.Nosol et al. (2020). Cryo-EM structures reveal distinct mechanisms of inhibition of the human multidrug transporter ABCB1. Proc Natl Acad Sci U S A, 117, 26245-26253. PubMed id: 33020312 DOI: 10.1073/pnas.2010264117

Date:

25-Aug-20 Release date: 14-Oct-20

Protein chain

P08183  (MDR1_HUMAN) -  ATP-dependent translocase ABCB1 from Homo sapiens

Seq: 1280 a.a.

Struc: 1164 a.a.*

Protein chain

A2NHM3  (A2NHM3_MOUSE) -  If kappa light chain (Fragment) from Mus musculus

Seq: 219 a.a.

Struc: 214 a.a.*

Protein chain

No UniProt id for this chain

Struc: 218 a.a.

* PDB and UniProt seqs differ at 8 residue positions (black crosses)

Enzyme reactions

• Enzyme class 2: Chain A: E.C.7.6.2.1 - P-type phospholipid transporter.
• Reaction: ATP + H2O + phospholipidSide 1 = ADP + phosphate + phospholipidSide 2
• Enzyme class 3: Chain A: 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.2010264117

Proc Natl Acad Sci U S A 117:26245-26253 (2020)

PubMed id: 33020312

Cryo-EM structures reveal distinct mechanisms of inhibition of the human multidrug transporter ABCB1.

K.Nosol, K.Romane, R.N.Irobalieva, A.Alam, J.Kowal, N.Fujita, K.P.Locher.

ABSTRACT

ABCB1 detoxifies cells by exporting diverse xenobiotic compounds, thereby limiting drug disposition and contributing to multidrug resistance in cancer cells. Multiple small-molecule inhibitors and inhibitory antibodies have been developed for therapeutic applications, but the structural basis of their activity is insufficiently understood. We determined cryo-EM structures of nanodisc-reconstituted, human ABCB1 in complex with the Fab fragment of the inhibitory, monoclonal antibody MRK16 and bound to a substrate (the antitumor drug vincristine) or to the potent inhibitors elacridar, tariquidar, or zosuquidar. We found that inhibitors bound in pairs, with one molecule lodged in the central drug-binding pocket and a second extending into a phenylalanine-rich cavity that we termed the "access tunnel." This finding explains how inhibitors can act as substrates at low concentration, but interfere with the early steps of the peristaltic extrusion mechanism at higher concentration. Our structural data will also help the development of more potent and selective ABCB1 inhibitors.