Snapshots of ligand entry, malleable binding and induced helical movement in P-glycoprotein

Szewczyk, Paul; Tao, Houchao; McGrath, Aaron P.; Villaluz, Mark; Rees, Steven D.; Lee, Sungchang; Doshi, Rupak; Urbatsch, Ina L.; Zhang, Qinghai; Chang, Geoffrey

doi:10.1107/s1399004715000978

Cited by 160 publications

(219 citation statements)

References 56 publications

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“…The larger structural differences are found in several loop regions in both NBDs, in the C-terminal helix of TmrB, increasing linearly toward the terminus, and in the periplasmic loop; these are all regions that would be expected to be less defined in the lower-resolution model and could not be modeled accurately in the cryo-EM map. Furthermore, parts of TM6 of TmrA, as well as in TM2, TM4, and TM5 of TmrB, also showed some variability with regard to the crystal structure; however, TM4 or its equivalent has been observed to be highly variable in several X-ray structures of ABC transporters (17)(18)(19). It is unclear whether the described differences between the cryo-EM model and the X-ray structure are due to a minor conformational change, caused by different experimental environments (cryo-EM vs. crystallography), or due to the limited resolution of the cryo-EM data.…”

Section: Resultsmentioning

confidence: 99%

Crystal structure and mechanistic basis of a functional homolog of the antigen transporter TAP

Noll

Thomas

Herbring

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

108

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ABC transporters form one of the largest protein superfamilies in all domains of life, catalyzing the movement of diverse substrates across membranes. In this key position, ABC transporters can mediate multidrug resistance in cancer therapy and their dysfunction is linked to various diseases. Here, we describe the 2.7-Å X-ray structure of heterodimeric Thermus thermophilus multidrug resistance proteins A and B (TmrAB), which not only shares structural homology with the antigen translocation complex TAP, but is also able to restore antigen processing in human TAP-deficient cells. TmrAB exhibits a broad peptide specificity and can concentrate substrates several thousandfold, using only one single active ATP-binding site. In our structure, TmrAB adopts an asymmetric inward-facing state, and we show that the C-terminal helices, arranged in a zipper-like fashion, play a crucial role in guiding the conformational changes associated with substrate transport. In conclusion, TmrAB can be regarded as a model system for asymmetric ABC exporters in general, and for TAP in particular.ABC transporter | conformational dynamics | membrane proteins | peptide transport | transporter associated with antigen processing

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Section: Resultsmentioning

confidence: 99%

Crystal structure and mechanistic basis of a functional homolog of the antigen transporter TAP

Noll

Thomas

Herbring

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

108

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“…A mouse ABCB1a crystal structure (PDB ID: 4Q9I) [12] was used to construct a human ABCB1 homology model. Maestro Elements was used to prepare the ligands.…”

Section: Molecular Dockingmentioning

confidence: 99%

Experimental and Simulation Identification of Xanthohumol as an Inhibitor and Substrate of ABCB1

Liu

Hoag

et al. 2018

Applied Sciences

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Xanthohumol (XN) is a well-known prenylated flavonoid found in Humulus lupulus L. It is involved in several pharmacological activities, including the sensitization of doxorubicin-resistant breast cancer (MCF-7/ADR) cells to doxorubicin (DOX) through a reduction in cell viability and stemness. In the present study, we revealed another mechanism to further explain the reverse of the drug resistance of XN. In the MCF-7/ADR cell line, we found that XN inhibited the efflux functions of ATP-binding cassette subfamily B member 1 (ABCB1). We also observed that XN was a substrate of ABCB1 and stimulated its ATPase activity. Moreover, our results revealed that XN showed a synergic effect with the ABCB1 substrate colchicine (COL) in the MCF-7/ADR cell line. Further, we showed that XN bound to the central transmembrane domain (TMD) site, overlapping with the DOX binding site. This mechanism was supported by molecular modeling and simulation data, which revealed that XN bound to the ABCB1 transmembrane domain, where doxorubicin also binds, and its binding affinity was stronger than that of doxorubicin, resulting in less protein and ligand position fluctuation. These results support the XN-induced reversal of drug resistance via the inhibition of ABCB1-mediated transport of doxorubicin, stimulating ABCB1 ATPase activity and acting as a substrate of ABCB1.

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“…However, electron density in the low resolution electron cryo-microscopy single particle reconstruction envelope of TmrAB was assigned to the detergent micelle (9). In the low resolution crystal structure of the eukaryotic P-glycoprotein, no lipids were observed (10,11), but non-denaturing mass spectrometry identified tightly associated lipids and a clear dependence of ligand and lipid binding (12).…”

mentioning

confidence: 99%

Structural and Functional Basis for Lipid Synergy on the Activity of the Antibacterial Peptide ABC Transporter McjD

Mehmood

Corradi

Choudhury

et al. 2016

Journal of Biological Chemistry

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Snapshots of ligand entry, malleable binding and induced helical movement in P-glycoprotein

Abstract: Co-crystal structures of P-glycoprotein with a series of engineered ligands reveal multiple ligand-binding modes, a ligand-binding site on the outer surface of the transporter and a conformational change that may couple to ATP hydrolysis.

Cited by 160 publications

References 56 publications

Crystal structure and mechanistic basis of a functional homolog of the antigen transporter TAP

Crystal structure and mechanistic basis of a functional homolog of the antigen transporter TAP

Experimental and Simulation Identification of Xanthohumol as an Inhibitor and Substrate of ABCB1

Structural and Functional Basis for Lipid Synergy on the Activity of the Antibacterial Peptide ABC Transporter McjD

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