title: Molecular basis of the polyspecificity of P-glycoprotein (ABCB1): recent biochemical and structural studies.
abstract: ABCB1 (P-glycoprotein/P-gp) is an ATP-binding cassette transporter well known for its association with multidrug resistance in cancer cells. Powered by the hydrolysis of ATP, it effluxes structurally diverse compounds. In this chapter, we discuss current views on the molecular basis of the substrate polyspecificity of P-gp. One of the features that accounts for this property is the structural flexibility observed in P-gp. Several X-ray crystal structures of mouse P-gp have been published recently in the absence of nucleotide, with and without bound inhibitors. All the structures are in an inward-facing conformation exhibiting different degrees of domain separation, thus revealing a highly flexible protein. Biochemical and biophysical studies also demonstrate this flexibility in mouse as well as human P-gp. Site-directed mutagenesis has revealed the existence of multiple transport-active binding sites in P-gp for a single substrate. Thus, drugs can bind at either primary or secondary sites. Biochemical, molecular modeling, and structure-activity relationship studies suggest a large, common drug-binding pocket with overlapping sites for different substrates. We propose that in addition to the structural flexibility, the molecular or chemical flexibility also contributes to the binding of substrates to multiple sites forming the basis of polyspecificity.
authors: Center for Cancer Research, Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Eduardo E
authors: EE
authors: Chufan
authors: Center for Cancer Research, Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Hong-May
authors: HM
authors: Sim
authors: Center for Cancer Research, Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. Electronic address: ambudkar@helix.nih.gov.
authors: Suresh V
authors: SV
authors: Ambudkar
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D001692:Biological Transport / Q000502:physiology; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D018360:Crystallography, X-Ray; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011487:Protein Conformation
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D029742:Caenorhabditis elegans Proteins
keywords: ABC transporter; Drug-binding sites; Multidrug resistance; P-glycoprotein; Polyspecificity; Structural flexibility
references: Chem Rev. 2009 Jul;109(7):2989-3011
references: 19583429
references: J Biol Chem. 2000 Feb 25;275(8):5253-6
references: 10681495
references: Eur J Pharm Sci. 2006 Apr;27(5):392-400
references: 16352426
references: Biochem J. 2006 Jun 15;396(3):537-45
references: 16492138
references: J Biol Chem. 1997 Aug 22;272(34):21160-6
references: 9261121
references: Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9704-9
references: 23690617
references: J Med Chem. 2002 Dec 19;45(26):5671-86
references: 12477351
references: Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19005-10
references: 18024585
references: Nat Biotechnol. 2009 Jun;27(6):546-7
references: 19513059
references: Mol Pharmacol. 2000 Dec;58(6):1357-67
references: 11093774
references: ChemMedChem. 2013 May;8(5):748-62
references: 23564544
references: FEBS Lett. 1995 Dec 27;377(3):285-9
references: 8549739
references: J Biol Chem. 2001 Mar 23;276(12):8657-64
references: 11121420
references: Trends Biochem Sci. 2014 Jan;39(1):8-16
references: 24316304
references: FEBS J. 2014 Feb;281(3):673-82
references: 24219411
references: Biochem J. 2006 Oct 15;399(2):351-9
references: 16813563
references: J Biol Chem. 2002 Nov 15;277(46):44332-8
references: 12223492
references: Adv Drug Deliv Rev. 1999 Apr 5;36(2-3):179-194
references: 10837715
references: Annu Rev Biochem. 1993;62:385-427
references: 8102521
references: Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2515-20
references: 10716986
references: Biochemistry. 2005 Jan 18;44(2):643-55
references: 15641790
references: J Chem Inf Model. 2011 Jun 27;51(6):1315-24
references: 21604687
references: PLoS One. 2011;6(10):e25815
references: 21991360
references: Eur J Biochem. 1997 Nov 15;250(1):130-7
references: 9432000
references: J Biol Chem. 2000 Dec 15;275(50):39272-8
references: 11013259
references: Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9710-5
references: 23716676
references: Nature. 2006 Sep 14;443(7108):180-5
references: 16943773
references: J Med Chem. 2002 Apr 25;45(9):1737-40
references: 11960484
references: Biochem Biophys Res Commun. 2010 May 7;395(3):436-40
references: 20394729
references: J Biol Chem. 2003 Jun 6;278(23):20449-52
references: 12711602
references: PLoS Comput Biol. 2011 Jun;7(6):e1002083
references: 21731480
references: J Biol Chem. 1992 Dec 5;267(34):24248-52
references: 1360010
references: J Biol Chem. 1995 Jan 13;270(2):843-8
references: 7822320
references: Eur J Biochem. 1999 Feb;259(3):841-50
references: 10092872
references: Biochemistry. 2013 Oct 15;52(41):7327-38
references: 24053441
references: J Biol Chem. 2011 Mar 25;286(12):10476-82
references: 21278250
references: Mol Pharm. 2014 Jul 7;11(7):2313-22
references: 24865254
references: Expert Opin Drug Metab Toxicol. 2008 Sep;4(9):1167-80
references: 18721111
references: J Membr Biol. 2000 Feb 1;173(3):203-14
references: 10667916
references: Science. 2014 Mar 7;343(6175):1133-6
references: 24604198
references: FEBS Lett. 2007 Sep 4;581(22):4217-22
references: 17706648
references: Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13386-91
references: 23901103
references: Curr Opin Struct Biol. 2007 Aug;17(4):412-8
references: 17723295
references: Biochemistry. 2005 Oct 25;44(42):14020-9
references: 16229491
references: J Biol Chem. 2001 May 4;276(18):14972-9
references: 11279063
references: FEBS Lett. 2006 Feb 13;580(4):1056-63
references: 16380120
references: Eur J Biochem. 1998 May 15;254(1):181-8
references: 9652412
references: Nature. 2012 Oct 25;490(7421):566-9
references: 23000902
references: EMBO J. 1995 May 1;14(9):1858-66
references: 7743993
references: J Biol Chem. 1993 May 25;268(15):11417-25
references: 8098711
references: FEBS J. 2014 May;281(9):2190-2201
references: 24597976
references: Science. 2009 Mar 27;323(5922):1718-22
references: 19325113
references: Trends Biochem Sci. 2010 Jan;35(1):36-42
references: 19819701
references: J Biol Chem. 2003 Apr 18;278(16):13603-6
references: 12609990
references: J Chem Inf Model. 2007 Nov-Dec;47(6):2429-38
references: 17956085
references: J Biol Chem. 1999 Aug 27;274(35):24759-65
references: 10455147
references: ChemMedChem. 2013 Oct;8(10):1701-13
references: 23943604
references: Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10594-9
references: 9380680
references: Chembiochem. 2011 Apr 11;12(6):868-73
references: 21387512
references: J Biol Chem. 1992 Mar 25;267(9):5731-4
references: 1348245
references: Nature. 1966 Aug 27;211(5052):969-70
references: 5968307
references: J Biol Chem. 1997 Dec 19;272(51):31945-8
references: 9405384
references: Biochim Biophys Acta. 1976 Nov 11;455(1):152-62
references: 990323
references: Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
references: 9254694
references: J Biol Chem. 2012 Jan 6;287(2):1112-27
references: 22086917
references: Mol Pharmacol. 2011 Mar;79(3):443-52
references: 21177413
references: ChemMedChem. 2009 Nov;4(11):1883-96
references: 19768722
references: Mol Pharmacol. 2005 Feb;67(2):365-74
references: 15509712
references: J Pharmacol Exp Ther. 1994 Jul;270(1):1-7
references: 7913494
references: Genome Biol. 2004;5(3):R15
references: 15003118
references: ChemMedChem. 2007 Dec;2(12):1783-8
references: 17994597
references: Mol Pharmacol. 2014 Mar;85(3):420-8
references: 24366667
references: Eur J Biochem. 1998 Jan 15;251(1-2):252-61
references: 9492291
references: PLoS One. 2013 Dec 05;8(12):e82463
references: 24349290
references: J Biol Chem. 2013 Jun 28;288(26):19211-20
references: 23658020
references: Protein Sci. 2014 Jan;23(1):34-46
references: 24155053
references: Front Oncol. 2014 Mar 03;4:41
references: 24624364
references: Annu Rev Pharmacol Toxicol. 1999;39:361-98
references: 10331089