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  • 1
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    Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-03-28
    Description: P-glycoprotein (P-gp) detoxifies cells by exporting hundreds of chemically unrelated toxins but has been implicated in multidrug resistance (MDR) in the treatment of cancers. Substrate promiscuity is a hallmark of P-gp activity, thus a structural description of poly-specific drug-binding is important for the rational design of anticancer drugs and MDR inhibitors. The x-ray structure of apo P-gp at 3.8 angstroms reveals an internal cavity of approximately 6000 angstroms cubed with a 30 angstrom separation of the two nucleotide-binding domains. Two additional P-gp structures with cyclic peptide inhibitors demonstrate distinct drug-binding sites in the internal cavity capable of stereoselectivity that is based on hydrophobic and aromatic interactions. Apo and drug-bound P-gp structures have portals open to the cytoplasm and the inner leaflet of the lipid bilayer for drug entry. The inward-facing conformation represents an initial stage of the transport cycle that is competent for drug binding.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720052/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720052/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Aller, Stephen G -- Yu, Jodie -- Ward, Andrew -- Weng, Yue -- Chittaboina, Srinivas -- Zhuo, Rupeng -- Harrell, Patina M -- Trinh, Yenphuong T -- Zhang, Qinghai -- Urbatsch, Ina L -- Chang, Geoffrey -- F32 GM078914/GM/NIGMS NIH HHS/ -- F32 GM078914-03/GM/NIGMS NIH HHS/ -- GM073197/GM/NIGMS NIH HHS/ -- GM078914/GM/NIGMS NIH HHS/ -- GM61905/GM/NIGMS NIH HHS/ -- P50 GM073197/GM/NIGMS NIH HHS/ -- P50 GM073197-050002/GM/NIGMS NIH HHS/ -- R01 GM061905/GM/NIGMS NIH HHS/ -- R01 GM061905-09/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2009 Mar 27;323(5922):1718-22. doi: 10.1126/science.1168750.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, Scripps Research Institute, 10550 North Torrey Pines Road, CB105, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19325113" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Amino Acid Sequence ; Animals ; Apoproteins/chemistry/metabolism ; Binding Sites ; Cell Membrane/chemistry ; Crystallography, X-Ray ; Hydrophobic and Hydrophilic Interactions ; Lipid Bilayers/chemistry ; Mice ; Models, Molecular ; Molecular Sequence Data ; P-Glycoprotein/antagonists & inhibitors/*chemistry/*metabolism ; Peptides, Cyclic/*chemistry/*metabolism ; Protein Binding ; Protein Conformation ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Stereoisomerism ; Verapamil/metabolism/pharmacology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    Crystal structure of the human sterol transporter ABCG5/ABCG8 (2016)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2016-05-05
    Description: ATP binding cassette (ABC) transporters play critical roles in maintaining sterol balance in higher eukaryotes. The ABCG5/ABCG8 heterodimer (G5G8) mediates excretion of neutral sterols in liver and intestines. Mutations disrupting G5G8 cause sitosterolaemia, a disorder characterized by sterol accumulation and premature atherosclerosis. Here we use crystallization in lipid bilayers to determine the X-ray structure of human G5G8 in a nucleotide-free state at 3.9 A resolution, generating the first atomic model of an ABC sterol transporter. The structure reveals a new transmembrane fold that is present in a large and functionally diverse superfamily of ABC transporters. The transmembrane domains are coupled to the nucleotide-binding sites by networks of interactions that differ between the active and inactive ATPases, reflecting the catalytic asymmetry of the transporter. The G5G8 structure provides a mechanistic framework for understanding sterol transport and the disruptive effects of mutations causing sitosterolaemia.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Jyh-Yeuan -- Kinch, Lisa N -- Borek, Dominika M -- Wang, Jin -- Wang, Junmei -- Urbatsch, Ina L -- Xie, Xiao-Song -- Grishin, Nikolai V -- Cohen, Jonathan C -- Otwinowski, Zbyszek -- Hobbs, Helen H -- Rosenbaum, Daniel M -- GM053163/GM/NIGMS NIH HHS/ -- GM094575/GM/NIGMS NIH HHS/ -- GM113050/GM/NIGMS NIH HHS/ -- GM117080/GM/NIGMS NIH HHS/ -- HL72304/HL/NHLBI NIH HHS/ -- P01-HL20948/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 May 4;533(7604):561-4. doi: 10.1038/nature17666.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA. ; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Cecil &Ida Green Center for Molecular, Computational and Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27144356" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Directed Evolution of P-glycoprotein Cysteines Reveals Site-specific, Non-conservative Substitutions that Preserve Multidrug Resistance (2014)
    Portland Press
    Details
    Publication Date: 2014-05-15
    Description: P-glycoprotein (Pgp) is a prototype ATP binding cassette transporter involved in multidrug resistance of cancer. We used directed evolution to replace six cytoplasmic cysteine (Cys) residues in Pgp with all twenty standard amino acids and selected for active mutants. From a pool of 75,000 transformants for each block of three Cys, we identified multiple mutants that preserved drug resistance and yeast mating activity. The most frequent substitutions were glycine and serine for C427 (24% and 20%, respectively) and C1070 (37% and 25%) of the Walker A motifs in the nucleotide binding domains (NBDs), C1223 in NBD2 (25% and 8%), and C638 in the linker region (24% and 16%), whereas close-by C669 tolerated glycine (16%) and alanine (14%), but not serine (absent). C1121 in NBD2 showed a clear preference for positively charged arginine (38%) suggesting a salt bridge with E269 in the intracellular loop ICL2 may stabilize domain interactions. In contrast, three Cys residues in transmembrane α-helices could be successfully replaced by alanine. The resulting Cys-less Pgp was fully active in yeast cells, and purified proteins displayed drug-stimulated ATPase activities indistinguishable from wild-type Pgp. Overall, directed evolution identified site-specific, non-conservative Cys substitutions that allowed building of a robust Cys-less Pgp, an invaluable new tool for future functional and structural studies, and that may guide the construction of other cysteine-less proteins where alanine and serine have proven unsuccessful.
    Print ISSN: 0144-8463
    Electronic ISSN: 1573-4935
    Topics: Biology , Chemistry and Pharmacology
    Published by Portland Press
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  • 4
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    Structures of P-glycoprotein reveal its conformational flexibility and an epitope on the nucleotide-binding domain (2013)
    National Academy of Sciences
    Details
    Publication Date: 2013-07-30
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 5
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    P-gp structures reveal flexibility and an epitope [Biophysics and Computational Biology] (2013)
    National Academy of Sciences
    Details
    Publication Date: 2013-08-14
    Description: P-glycoprotein (P-gp) is one of the best-known mediators of drug efflux-based multidrug resistance in many cancers. This validated therapeutic target is a prototypic, plasma membrane resident ATP-Binding Cassette transporter that pumps xenobiotic compounds out of cells. The large, polyspecific drug-binding pocket of P-gp recognizes a variety of structurally unrelated compounds....
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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