title: Where does amantadine bind to the influenza virus M2 proton channel?
abstract: Structures of the influenza A virus M2 proton channel in the open conformation have been determined by X-ray crystallography, and in the closed conformation by NMR. Whereas the X-ray structure shows a single inhibitor molecule in the middle of the channel, four inhibitor molecules bind the channel's outer surface in the NMR structure. In both structures, the strongest hot spots (i.e., regions that contribute substantially to the free energy of binding any potential ligand) lie inside the pore, and other hot spots are found at exterior locations. By considering all available models, we propose the primary drug binding site is inside the pore, but that exterior binding occurs under appropriate conditions.
authors.affiliation: Department of Biomedical Engineering, Boston University, 44 Cummington Street, Boston, MA 02215, USA.
authors.forename: Dima
authors.initials: D
authors.lastname: Kozakov
authors.forename: Gwo-Yu
authors.initials: GY
authors.lastname: Chuang
authors.forename: Dmitri
authors.initials: D
authors.lastname: Beglov
authors.forename: Sandor
authors.initials: S
authors.lastname: Vajda
mesh_terms: D000547:Amantadine / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D009980:Influenza A virus / Q000187:drug effects / Q000378:metabolism*; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000086082:Viroporin Proteins
chemical_list: D000547:Amantadine; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins
references.citation: J Am Chem Soc. 2002 Mar 20;124(11):2450-1
references.pmid: 11890789
references.citation: Biophys J. 2000 Aug;79(2):767-75
references.pmid: 10920010
references.citation: Biophys J. 2007 Jul 1;93(1):276-83
references.pmid: 17434944
references.citation: Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1069-74
references.pmid: 19144924
references.citation: Proteins. 2004 May 1;55(2):251-7
references.pmid: 15048819
references.citation: Biochemistry. 2002 Nov 5;41(44):13170-7
references.pmid: 12403618
references.citation: Biophys J. 2008 Dec 15;95(12):5627-36
references.pmid: 18835906
references.citation: J Med Chem. 2005 Apr 7;48(7):2518-25
references.pmid: 15801841
references.citation: J Physiol. 1996 Jul 15;494 ( Pt 2):329-36
references.pmid: 8841994
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10967-72
references.pmid: 18669647
references.citation: Nature. 2008 Jan 31;451(7178):591-5
references.pmid: 18235503
references.citation: Mol Biosyst. 2007 Jan;3(1):18-23
references.pmid: 17216051
references.citation: JAMA. 2006 Feb 22;295(8):891-4
references.pmid: 16456087
references.citation: Biophys J. 2009 Nov 18;97(10):2846-53
references.pmid: 19917240
references.citation: J Biol Chem. 2002 Oct 18;277(42):39880-6
references.pmid: 12183461
references.citation: Biochim Biophys Acta. 2007 Dec;1768(12):3162-70
references.pmid: 17936720
references.citation: Proc Natl Acad Sci U S A. 2009 May 5;106(18):7379-84
references.pmid: 19383794
references.citation: Biophys J. 2003 Nov;85(5):2900-18
references.pmid: 14581194
references.citation: J Mol Model. 2009 Nov;15(11):1317-28
references.pmid: 19377895
references.citation: Biophys J. 2007 Jun 15;92(12):4335-43
references.pmid: 17384070
references.citation: Trends Microbiol. 1995 Jul;3(7):271
references.pmid: 7551640
references.citation: J Mol Biol. 2009 Jan 30;385(4):1127-41
references.pmid: 19061899
references.citation: Biophys J. 1997 Nov;73(5):2511-7
references.pmid: 9370444
references.citation: Protein Sci. 2001 Nov;10(11):2241-50
references.pmid: 11604531
references.citation: Bioinformatics. 2005 May 1;21(9):1908-16
references.pmid: 15701681
references.citation: Biochim Biophys Acta. 2007 Dec;1768(12):3098-106
references.pmid: 17961504
references.citation: Biophys J. 2008 Feb 15;94(4):1295-302
references.pmid: 17890391
references.citation: J Med Chem. 2007 Mar 22;50(6):1231-40
references.pmid: 17305325
references.citation: Nat Biotechnol. 1996 May;14(5):595-9
references.pmid: 9630949
references.citation: Nature. 2008 Jan 31;451(7178):532-3
references.pmid: 18235492
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13533-7
references.pmid: 12370417
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13311-6
references.pmid: 19633188
references.citation: J Biomol NMR. 2004 Jul;29(3):299-308
references.pmid: 15213428
references.citation: J Infect Dis. 2007 Jul 15;196(2):249-57
references.pmid: 17570112
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1483-8
references.pmid: 18230730
references.citation: Biophys J. 2008 Jan 15;94(2):434-45
references.pmid: 17827230
references.citation: Nature. 2008 Jan 31;451(7178):596-9
references.pmid: 18235504
references.citation: Nature. 2010 Feb 4;463(7281):689-92
references.pmid: 20130653
references.citation: Cell. 1992 May 15;69(4):577-8
references.pmid: 1375129
references.citation: Bioinformatics. 2009 Mar 1;25(5):621-7
references.pmid: 19176554
references.citation: Virology. 1991 Feb;180(2):617-24
references.pmid: 1989386
references.citation: N Engl J Med. 2006 Feb 23;354(8):785-8
references.pmid: 16495389
references.citation: Protein Sci. 2005 Apr;14(4):856-61
references.pmid: 15741338
references.citation: J Mol Biol. 2000 Jan 7;295(1):117-25
references.pmid: 10623512
references.citation: Structure. 2009 Feb 13;17(2):247-54
references.pmid: 19217395