7A6C

Nanodisc reconstituted human ABCB1 in complex with MRK16 Fab and elacridar

Summary for 7A6C

• Entry DOI: 10.2210/pdb7a6c/pdb
• Related: 7A65 7A69
• EMDB information: 11670
• Descriptor: Multidrug resistance protein 1, If kappa light chain, MRK16 Fab-fragment heavy chain, ... (5 entities in total)
• Functional Keywords: p-glycoprotein, mdr1, nanodisc, transport protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 194177.60

Authors

Nosol, K.,Locher, K.P. (deposition date: 2020-08-25, release date: 2020-10-14, Last modification date: 2024-11-13)

Primary citation

Nosol, K.,Romane, K.,Irobalieva, R.N.,Alam, A.,Kowal, J.,Fujita, N.,Locher, K.P.
Cryo-EM structures reveal distinct mechanisms of inhibition of the human multidrug transporter ABCB1.
Proc.Natl.Acad.Sci.USA, 117:26245-26253, 2020

PubMed 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.

PubMed: 33020312
DOI: 10.1073/pnas.2010264117

Experimental method

ELECTRON MICROSCOPY (3.6 Å)