Mechanism of partial agonism at the GluR2 AMPA receptor: Measurements of lobe orientation in solution.
The mechanism by which the binding of a neurotransmitter to a receptor leads to channel opening is a central issue in molecular neurobiology. The structure of the agonist binding domain of ionotropic glutamate receptors has led to an improved understanding of the changes in structure that accompany agonist binding and have provided important clues about the link between these structural changes and channel activation and desensitization. However, because the binding domain has exhibited different structures under different crystallization conditions, understanding the structure in the absence of crystal packing is of considerable importance. The orientation of the two lobes of the binding domain in the presence of a full agonist, an antagonist, and several partial agonists was measured using NMR spectroscopy by employing residual dipolar couplings. For some partial agonists, the solution conformation differs from that observed in the crystal. A model of channel activation based on the results is discussed.
Maltsev
Alexander S
AS
Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.
Ahmed
Ahmed H
AH
Fenwick
Michael K
MK
Jane
David E
DE
Oswald
Robert E
RE
D000409:Alanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D018360:Crystallography, X-Ray; D018698:Glutamic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007608:Kainic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D018091:Receptors, AMPA / Q000819:agonists* / Q000737:chemistry* / Q000378:metabolism; D012996:Solutions; D014498:Uracil / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D018091:Receptors, AMPA; D012996:Solutions; C002872:willardiine; D018698:Glutamic Acid; D014498:Uracil; D000409:Alanine; C104722:glutamate receptor ionotropic, AMPA 2; D007608:Kainic Acid
J Biomol NMR. 2001 Oct;21(2):141-51
11727977
Proteins. 2009 May 15;75(3):628-37
19003990
J Neurosci. 1992 Feb;12(2):595-606
1371315
Pharmacol Rev. 1999 Mar;51(1):7-61
10049997
Nature. 2002 May 16;417(6886):245-53
12015593
Neuron. 2005 Jul 7;47(1):71-84
15996549
Phys Biol. 2005 Nov 09;2(4):S137-47
16280619
Nature. 2006 Mar 23;440(7083):456-62
16554805
J Am Chem Soc. 2003 Jul 30;125(30):9179-91
15369375
Structure. 2007 Oct;15(10):1203-14
17937910
Nat Struct Biol. 1997 Jun;4(6):443-9
9187651
J Am Chem Soc. 2001 Feb 21;123(7):1416-24
11456715
Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13431-6
9391042
J Neurosci. 2008 Jan 23;28(4):932-43
18216201
J Mol Biol. 2008 May 2;378(3):673-85
18387631
Neuron. 2000 Oct;28(1):165-81
11086992
Biochemistry. 2002 Aug 20;41(33):10472-81
12173934
J Neurosci. 2005 Apr 13;25(15):3752-62
15829627
Biochemistry. 2003 May 13;42(18):5201-13
12731861
Nat Struct Biol. 1997 Sep;4(9):732-8
9303001
Nature. 1998 Oct 29;395(6705):913-7
9804426
Biochemistry. 2005 Mar 8;44(9):3410-7
15736951
J Biol Chem. 2007 Apr 27;282(17):12773-84
17337449
J Biomol NMR. 1995 Nov;6(3):277-93
8520220
Biophys J. 2002 Feb;82(2):676-83
11806910
J Biomol NMR. 2000 Apr;16(4):329-37
10826884
Biomol NMR Assign. 2007 Dec;1(2):241-3
19636875
Nat Neurosci. 2003 Aug;6(8):803-10
12872125
Methods Enzymol. 2004;380:170-87
15051337
Biochemistry. 2007 Feb 6;46(5):1343-9
17260963
Biochemistry. 2008 Jan 8;47(1):398-404
18081322
J Med Chem. 1997 Oct 24;40(22):3645-50
9357531
EMBO J. 2003 Jun 16;22(12):2873-85
12805203
Mol Neurobiol. 1996 Feb;12(1):1-11
8732537
Annu Rev Neurosci. 1994;17:31-108
8210177
Science. 1998 Jun 5;280(5369):1596-9
9616121
J Mol Biol. 2000 Feb 4;295(5):1265-73
10653702
J Mol Graph Model. 2002 Dec;21(3):181-3
12463636
J Magn Reson. 2003 Jan;160(1):65-73
12565051
Proc Natl Acad Sci U S A. 2003 May 13;100(10):5736-41
12730367
J Am Chem Soc. 2002 Oct 9;124(40):12020-30
12358549
Adv Protein Chem. 2004;68:313-49
15500865
J Med Chem. 2005 Dec 1;48(24):7867-81
16302825