7a6e

Nanodisc reconstituted human ABCB1 in complex with MRK16 Fab and tariquidar

spinqualitylabelsall models 7a6e, resolution 3.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7a6e is a 3 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.6Å Ligands: CLR, R1H Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. Cryo-EM structures reveal distinct mechanisms of inhibition of the human multidrug transporter ABCB1.,Nosol K, Romane K, Irobalieva RN, Alam A, Kowal J, Fujita N, Locher KP Proc Natl Acad Sci U S A. 2020 Oct 5. pii: 2010264117. doi:, 10.1073/pnas.2010264117. PMID:33020312 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also ABC transporter 3D structures Antibody 3D structures Monoclonal Antibodies 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA