Structural determinants for interaction of partial agonists with acetylcholine binding protein and neuronal alpha7 nicotinic acetylcholine receptor.
The pentameric acetylcholine-binding protein (AChBP) is a soluble surrogate of the ligand binding domain of nicotinic acetylcholine receptors. Agonists bind within a nest of aromatic side chains contributed by loops C and F on opposing faces of each subunit interface. Crystal structures of Aplysia AChBP bound with the agonist anabaseine, two partial agonists selectively activating the alpha7 receptor, 3-(2,4-dimethoxybenzylidene)-anabaseine and its 4-hydroxy metabolite, and an indole-containing partial agonist, tropisetron, were solved at 2.7-1.75 A resolution. All structures identify the Trp 147 carbonyl oxygen as the hydrogen bond acceptor for the agonist-protonated nitrogen. In the partial agonist complexes, the benzylidene and indole substituent positions, dictated by tight interactions with loop F, preclude loop C from adopting the closed conformation seen for full agonists. Fluctuation in loop C position and duality in ligand binding orientations suggest molecular bases for partial agonism at full-length receptors. This study, while pointing to loop F as a major determinant of receptor subtype selectivity, also identifies a new template region for designing alpha7-selective partial agonists to treat cognitive deficits in mental and neurodegenerative disorders.
Hibbs
Ryan E
RE
Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
Sulzenbacher
Gerlind
G
Shi
Jianxin
J
Talley
Todd T
TT
Conrod
Sandrine
S
Kem
William R
WR
Taylor
Palmer
P
Marchot
Pascale
P
Bourne
Yves
Y
D000109:Acetylcholine / Q000378:metabolism; D000691:Anabasine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001048:Aplysia / Q000737:chemistry*; D001597:Benzylidene Compounds / Q000737:chemistry / Q000378:metabolism; D002352:Carrier Proteins / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D018722:Nicotinic Agonists / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism; D000077526:Tropisetron
D001597:Benzylidene Compounds; D002352:Carrier Proteins; D007211:Indoles; D018722:Nicotinic Agonists; D011725:Pyridines; D000077526:Tropisetron; C088936:3-(2,4-dimethoxybenzylidene)anabaseine; C091713:anabaseine; D000691:Anabasine; D000109:Acetylcholine
J Struct Biol. 1999 Apr-May;125(2-3):156-65
10222271
Curr Opin Anaesthesiol. 2006 Dec;19(6):606-11
17093363
Biochem Pharmacol. 2007 Feb 15;73(4):459-68
16979139
J Pharmacol Exp Ther. 2006 Jun;317(3):1276-84
16551836
Mol Pharmacol. 2004 Jul;66(1):14-24
15213292
Bioorg Med Chem Lett. 2001 Feb 12;11(3):319-21
11212100
Trends Pharmacol Sci. 1993 Jul;14(7):270-5
8105597
Proc Natl Acad Sci U S A. 2008 May 27;105(21):7606-11
18477694
Nature. 2009 Jan 1;457(7225):115-8
18987630
J Biol Chem. 2004 Jun 4;279(23):24197-202
15069068
Biochem Pharmacol. 1973 Dec 1;22(23):3099-108
4202581
Brain Res. 1998 Jan 1;779(1-2):359-63
9473725
Nat Struct Biol. 1999 May;6(5):458-63
10331874
Biochemistry. 2000 Dec 19;39(50):15388-98
11112524
Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3
15299374
J Biol Chem. 2006 Apr 28;281(17):12170-7
16484218
J Pharmacol Exp Ther. 2001 Dec;299(3):1112-9
11714901
Neuron. 2004 Mar 25;41(6):907-14
15046723
J Pharmacol Exp Ther. 1997 Dec;283(3):979-92
9399967
Nat Rev Neurosci. 2002 Feb;3(2):102-14
11836518
EMBO J. 2005 Apr 20;24(8):1512-22
15791209
Br J Pharmacol Chemother. 1956 Dec;11(4):379-93
13383117
Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
15299926
Nucleic Acids Res. 2007 Jul;35(Web Server issue):W375-83
17452350
Br J Pharmacol. 1992 Feb;105(2):500-4
1559139
Neuropharmacology. 2004 Jun;46(7):1023-38
15081799
Nature. 2007 Jan 4;445(7123):116-9
17167423
Neuropharmacology. 1995 Jun;34(6):583-90
7566493
Methods Enzymol. 1997;276:307-26
27754618
Nature. 2008 Mar 20;452(7185):375-9
18322461
Biochemistry. 2006 Jul 25;45(29):8894-902
16846232
J Mol Biol. 2005 Mar 4;346(4):967-89
15701510
Nature. 2001 May 17;411(6835):269-76
11357122
Mol Pharmacol. 2004 Jan;65(1):56-67
14722237
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
15572765
Nature. 2009 Jan 1;457(7225):111-4
18987633
Neurosci Lett. 2005 Apr 22;378(3):140-4
15781147
Nat Neurosci. 2007 Aug;10(8):953-62
17643119
Science. 2005 Jun 3;308(5727):1424-8
15933191
Arch Gen Psychiatry. 2006 Jun;63(6):630-8
16754836
Nature. 2004 Aug 19;430(7002):896-900
15318223
J Biol Chem. 2003 Jun 20;278(25):23020-6
12682067
J Biol Chem. 2002 Nov 1;277(44):41299-302
12235129
Am J Psychiatry. 2008 Aug;165(8):1040-7
18381905
Nature. 2008 Aug 7;454(7205):722-7
18633353
EMBO J. 2005 Oct 19;24(20):3635-46
16193063
J Pharmacol Exp Ther. 2009 May;329(2):791-807
19223664
Mol Pharmacol. 1995 Jan;47(1):164-71
7838125
Behav Brain Res. 2000 Aug;113(1-2):169-81
10942043