Imperial College London

DrMarkRosenberg

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Honorary Research Fellow
 
 
 
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Contact

 

mark.rosenberg

 
 
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Location

 

Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

14 results found

Rosenberg MF, Bikadi Z, Hazai E, Starborg T, Kelley L, Chayen N, Ford RC, Mao Qet al., 2015, Three-dimensional structure of the human breast cancer resistance protein (BCRP/ABCG2) in an inward-facing conformation, Acta Crystallographica Section D - Biological Crystallography, Vol: 71, Pages: 1725-1735, ISSN: 0907-4449

ABCG2 is an efflux drug transporter that plays an important role in drug resistance and drug disposition. In this study, the first three-dimensional structure of human full-length ABCG2 analysed by electron crystallography from two-dimensional crystals in the absence of nucleotides and transported substrates is reported at 2 nm resolution. In this state, ABCG2 forms a symmetric homodimer with a noncrystallographic twofold axis perpendicular to the two-dimensional crystal plane, as confirmed by subtomogram averaging. This configuration suggests an inward-facing configuration similar to murine ABCB1, with the nucleotide-binding domains (NBDs) widely separated from each other. In the three-dimensional map, densities representing the long cytoplasmic extensions from the transmembrane domains that connect the NBDs are clearly visible. The structural data have allowed the atomic model of ABCG2 to be refined, in which the two arms of the V-shaped ABCG2 homodimeric complex are in a more closed and narrower conformation. The structural data and the refined model of ABCG2 are compatible with the biochemical analysis of the previously published mutagenesis studies, providing novel insight into the structure and function of the transporter.Keywords: ABCG2; BCRP; ABC transporter; ATP-binding cassette transporter; cryo-electron microscopy; three-dimensional structure from two-dimensional crystals.

Journal article

Rosenberg MF, O'Ryan LP, Hughes G, Zhao Z, Aleksandrov LA, Riordan JR, Ford RCet al., 2011, The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), Journal of Biological Chemistry, Vol: 286, Pages: 42647-42654, ISSN: 0021-9258

Journal article

Ni Z, Bikadi Z, Shuster DL, Zhao C, Rosenberg MF, Mao Qet al., 2011, Identification of Proline Residues in or near the Transmembrane Helices of the Human Breast Cancer Resistance Protein (BCRP/ABCG2) That Are Important for Transport Activity and Substrate Specificity, Biochemistry, Vol: 50, Pages: 8057-8066, ISSN: 0006-2960

Journal article

Ni Z, Bikadi Z, Cai X, Rosenberg MF, Mao Qet al., 2010, Transmembrane helices 1 and 6 of the human breast cancer resistance protein (BCRP/ABCG2): identification of polar residues important for drug transport, American Journal of Physiology-Cell Physiology, Vol: 299, Pages: C1100-C1109, ISSN: 0363-6143

<jats:p> The human breast cancer resistance protein (BCRP/ABCG2) mediates efflux of drugs and xenobiotics. In this study, we investigated the role of polar residues within or near the predicted transmembrane α-helices 1 and 6 of BCRP in drug transport. We substituted Asn<jats:sup>387</jats:sup>, Gln<jats:sup>398</jats:sup>, Asn<jats:sup>629</jats:sup>, and Thr<jats:sup>642</jats:sup> with Ala, Thr<jats:sup>402</jats:sup> with Ala and Arg, and Tyr<jats:sup>645</jats:sup> with Phe, and the mutants were stably expressed in human embryonic kidney-293 or Flp-In-293 cells. Immunoblotting and confocal microscopy analysis revealed that all of the mutants were well expressed and predominantly targeted to the plasma membrane. While T402A and T402R showed a significant global reduction in the efflux of mitoxantrone, Hoechst 33342, and BODIPY-prazosin, N629A exhibited significantly increased efflux activities for all of the substrates. N387A and Q398A displayed significantly impaired efflux for mitoxantrone and Hoechst 33342, but not for BODIPY-prazosin. In contrast, T642A and Y645F showed a moderate reduction in Hoechst 33342 efflux only. Drug resistance profiles of human embryonic kidney-293 cells expressing the mutants generally correlated with the efflux data. Furthermore, N629A was associated with a marked increase, and N387A and T402A with a significant reduction, in BCRP ATPase activity. Mutations of some of the polar residues may cause conformational changes, as manifested by the altered binding of the 5D3 antibody to BCRP in the presence of prazosin. The inward-facing homology model of BCRP indicated that Thr<jats:sup>402</jats:sup> within transmembrane 1 may be important for helical interactions, and Asn<jats:sup>629</jats:sup> may be involved in BCRP-substrate interaction. In conclusion, we have demonstrated the functional importance of some of these polar resi

Journal article

Rosenberg MF, Oleschuk CJ, Wu P, Mao Q, Deeley RG, Cole SPC, Ford RCet al., 2010, Structure of a human multidrug transporter in an inward-facing conformation, Journal of Structural Biology, Vol: 170, Pages: 540-547, ISSN: 1047-8477

Journal article

Cai X, Bikadi Z, Ni Z, Lee E-W, Wang H, Rosenberg MF, Mao Qet al., 2010, Role of Basic Residues within or near the Predicted Transmembrane Helix 2 of the Human Breast Cancer Resistance Protein in Drug Transport, Journal of Pharmacology and Experimental Therapeutics, Vol: 333, Pages: 670-681, ISSN: 0022-3565

Journal article

Rosenberg MF, Bikadi Z, Chan J, Liu X, Ni Z, Cai X, Ford RC, Mao Qet al., 2010, The Human Breast Cancer Resistance Protein (BCRP/ABCG2) Shows Conformational Changes with Mitoxantrone, Structure, Vol: 18, Pages: 482-493, ISSN: 0969-2126

Journal article

BarillĂ  D, Rosenberg MF, Nobbmann U, Hayes Fet al., 2005, Bacterial DNA segregation dynamics mediated by the polymerizing protein ParF, The EMBO Journal, Vol: 24, Pages: 1453-1464, ISSN: 0261-4189

Journal article

Rosenberg MF, Callaghan R, Modok S, Higgins CF, Ford RCet al., 2005, Three-dimensional structure of P-glycoprotein - The transmembrane regions adopt an asymmetric configuration in the nucleotide-bound state, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 280, Pages: 2857-2862, ISSN: 0021-9258

Journal article

Rosenberg MF, Kamis AB, Callaghan R, Higgins CF, Ford RCet al., 2003, Three-dimensional structures of the mammalian multidrug resistance P-glycoprotein demonstrate major conformational changes in the transmembrane domains upon nucleotide binding, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 278, Pages: 8294-8299, ISSN: 0021-9258

Journal article

Rosenberg MF, Velarde G, Ford RC, Martin C, Berridge G, Kerr ID, Callaghan R, Schmidlin A, Wooding C, Linton KJ, Higgins CFet al., 2001, Repacking of the transmembrane domains of P-glycoprotein during the transport ATPase cycle, EMBO JOURNAL, Vol: 20, Pages: 5615-5625, ISSN: 0261-4189

Journal article

Ford RC, Velarde GS, Rosenberg MF, Powis SJ, Callaahan R, Mao QC, Higgins CFet al., 2001, ABC transporters under the microscope, Meeting of the Physiological-Society, Publisher: CAMBRIDGE UNIV PRESS, Pages: 2S-3S, ISSN: 0022-3751

Conference paper

Higgins CF, Callaghan R, Linton KJ, Rosenberg MF, Ford RCet al., 1997, Structure of the multidrug resistance P-glycoprotein, SEMINARS IN CANCER BIOLOGY, Vol: 8, Pages: 135-142, ISSN: 1044-579X

Journal article

Rosenberg MF, Callaghan R, Ford RC, Higgins CFet al., 1997, Structure of the multidrug resistance P-glycoprotein to 2.5 nm resolution determined by electron microscopy and image analysis, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 272, Pages: 10685-10694, ISSN: 0021-9258

Journal article

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