6FN4
Apo form of UIC2 Fab complex of human-mouse chimeric ABCB1 (ABCB1HM)
Summary for 6FN4
| Entry DOI | 10.2210/pdb6fn4/pdb |
| Related | 6FN1 |
| EMDB information | 4281 4282 |
| Descriptor | Apo form of Human-mouse chimeric ABCB1 (ABCB1HM) in complex with Antigen binding fragment of UIC2., UIC2 Antigen Binding Fragment Light chain, UIC2 Antigen binding fragment Heavy chain, ... (5 entities in total) |
| Functional Keywords | membrane transport protein abcb1 abc exporter small molecule inhibitor antibody complex, membrane protein |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 3 |
| Total formula weight | 191397.16 |
| Authors | Alam, A.,Locher, K.P. (deposition date: 2018-02-02, release date: 2018-02-21, Last modification date: 2024-10-16) |
| Primary citation | Alam, A.,Kung, R.,Kowal, J.,McLeod, R.A.,Tremp, N.,Broude, E.V.,Roninson, I.B.,Stahlberg, H.,Locher, K.P. Structure of a zosuquidar and UIC2-bound human-mouse chimeric ABCB1. Proc. Natl. Acad. Sci. U.S.A., 115:E1973-E1982, 2018 Cited by PubMed Abstract: The multidrug transporter ABCB1 (P-glycoprotein) is an ATP-binding cassette transporter that has a key role in protecting tissues from toxic insult and contributes to multidrug extrusion from cancer cells. Here, we report the near-atomic resolution cryo-EM structure of nucleotide-free ABCB1 trapped by an engineered disulfide cross-link between the nucleotide-binding domains (NBDs) and bound to the antigen-binding fragment of the human-specific inhibitory antibody UIC2 and to the third-generation ABCB1 inhibitor zosuquidar. Our structure reveals the transporter in an occluded conformation with a central, enclosed, inhibitor-binding pocket lined by residues from all transmembrane (TM) helices of ABCB1. The pocket spans almost the entire width of the lipid membrane and is occupied exclusively by two closely interacting zosuquidar molecules. The external, conformational epitope facilitating UIC2 binding is also visualized, providing a basis for its inhibition of substrate efflux. Additional cryo-EM structures suggest concerted movement of TM helices from both halves of the transporters associated with closing the NBD gap, as well as zosuquidar binding. Our results define distinct recognition interfaces of ABCB1 inhibitory agents, which may be exploited for therapeutic purposes. PubMed: 29440498DOI: 10.1073/pnas.1717044115 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (4.14 Å) |
Structure validation
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