Coarse-grained modeling of allosteric regulation in protein receptors.
Allosteric regulation provides highly specific ligand recognition and signaling by transmembrane protein receptors. Unlike functions of protein molecular machines that rely on large-scale conformational transitions, signal transduction in receptors appears to be mediated by more subtle structural motions that are difficult to identify. We describe a theoretical model for allosteric regulation in receptors that addresses a fundamental riddle of signaling: What are the structural origins of the receptor agonism (specific signaling response to ligand binding)? The model suggests that different signaling pathways in bovine rhodopsin or human beta(2)-adrenergic receptor can be mediated by specific structural motions in the receptors. We discuss implications for understanding the receptor agonism, particularly the recently observed "biased agonism" (selected activation of specific signaling pathways), and for developing rational structure-based drug-design strategies.
Balabin
Ilya A
IA
Department of Chemistry, Duke University, Durham, NC 27708, USA. ilya.balabin@duke.edu
Yang
Weitao
W
Beratan
David N
DN
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000465:Algorithms; D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008962:Models, Theoretical; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000378:metabolism*; D012243:Rhodopsin / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D008024:Ligands; D018343:Receptors, Adrenergic, beta-2; D012243:Rhodopsin
Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4689-94
19258456
Proteins. 2004 Nov 15;57(3):433-43
15382234
Protein Sci. 2008 Aug;17(8):1295-307
18560010
Trends Pharmacol Sci. 2007 Aug;28(8):407-15
17629960
Biochemistry. 1966 Jan;5(1):365-85
5938952
J Biol Chem. 2008 Feb 29;283(9):5669-76
18086673
EMBO J. 2008 Mar 5;27(5):727-35
18273062
J Mol Biol. 1965 May;12:88-118
14343300
Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11182-7
18678900
Cell. 2004 Mar 19;116(6):803-16
15035983
Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12570-5
14566052
Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10066-71
15218105
Curr Opin Struct Biol. 2003 Dec;13(6):748-57
14675554
Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9627-32
17517618
Nature. 2007 Dec 13;450(7172):1001-9
18075579
Biophys J. 2001 Jan;80(1):505-15
11159421
Nat Struct Mol Biol. 2006 Sep;13(9):831-8
16906160
Physiol Rev. 2001 Oct;81(4):1659-88
11581499
Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2175-80
17287347
J Mol Biol. 1997 Feb 14;266(1):195-214
9054980
BMC Struct Biol. 2008 Jan 30;8:5
18234095
J Mol Biol. 2005 Sep 30;352(4):807-22
16139299
Science. 2005 Apr 22;308(5721):512-7
15845844
Biophys J. 2007 Oct 1;93(7):2289-99
17557788
Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):4882-7
16551744
Science. 2008 Jun 13;320(5882):1429-30
18556537
J Biol Chem. 2004 Feb 27;279(9):8126-32
14660595
Nature. 2007 Dec 13;450(7172):983-90
18075577
Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):9988-93
18621717
Science. 2007 Nov 23;318(5854):1258-65
17962520
Phys Rev Lett. 1996 Aug 26;77(9):1905-1908
10063201
Mol Cell Proteomics. 2005 Dec;4(12):1959-67
16332734
Science. 2007 Nov 23;318(5854):1266-73
17962519
Structure. 2008 Jun;16(6):897-905
18547522
Mol Biosyst. 2008 Apr;4(4):287-92
18354781
Fundam Clin Pharmacol. 2005 Feb;19(1):45-56
15660959
Nat Chem Biol. 2008 Aug;4(8):474-82
18641628
Philos Trans R Soc Lond B Biol Sci. 2006 Aug 29;361(1472):1439-43
16873130
Nat Struct Biol. 2003 Jan;10(1):59-69
12483203
J Mol Biol. 2004 Sep 10;342(2):571-83
15327956
Biochem Soc Trans. 2004 Nov;32(Pt 5):873-7
15494038
Curr Opin Struct Biol. 2004 Dec;14(6):706-15
15582395
Biochemistry. 2008 Oct 21;47(42):11013-23
18821775
Proteins. 2004 Dec 1;57(4):783-91
15317024
J Biol Chem. 2008 Jan 25;283(4):2042-8
17998210
Proteins. 2007 Jun 1;67(4):886-96
17373706
Proc Natl Acad Sci U S A. 2006 May 16;103(20):7649-54
16684887
J Comput Aided Mol Des. 2006 Jul-Aug;20(7-8):405-16
17089205
Trends Pharmacol Sci. 2007 Aug;28(8):431-7
17644194
J Biol Chem. 2007 Aug 31;282(35):25677-86
17591774
Mol Syst Biol. 2006;2:2006.0019
16738564
Curr Protein Pept Sci. 2004 Apr;5(2):119-23
15078222