Test of the Binding Threshold Hypothesis for olfactory receptors: explanation of the differential binding of ketones to the mouse and human orthologs of olfactory receptor 912-93.
We tested the Binding Threshold Hypothesis (BTH) for activation of olfactory receptors (ORs): To activate an OR, the odorant must bind to the OR with binding energy above some threshold value. The olfactory receptor (OR) 912-93 is known experimentally to be activated by ketones in mouse, but is inactive to ketones in human, despite an amino acid sequence identity of approximately 66%. To investigate the origins of this difference, we used the MembStruk first-principles method to predict the tertiary structure of the mouse OR 912-93 (mOR912-93), and the HierDock first-principles method to predict the binding site for ketones to this receptor. We found that the strong binding of ketones to mOR912-93 is dominated by a hydrogen bond of the ketone carbonyl group to Ser105. All ketones predicted to have a binding energy stronger than EBindThresh = 26 kcal/mol were observed experimentally to activate this OR, while the two ketones predicted to bind more weakly do not. In addition, we predict that 2-undecanone and 2-dodecanone both bind sufficiently strongly to activate mOR912-93. A similar binding site for ketones was predicted in hOR912-93, but the binding is much weaker because the human ortholog has a Gly at the position of Ser105. We predict that mutating this Gly to Ser in human should lead to activation of hOR912-93 by these ketones. Experimental substantiations of the above predictions would provide further tests of the validity of the BTH, our predicted 3D structures, and our predicted binding sites for these ORs.
Hummel
Patrick
P
Materials and Process Simulation Center (MC 139-74), California Institute of Technology, Pasadena, CA 91125, USA.
Vaidehi
Nagarajan
N
Floriano
Wely B
WB
Hall
Spencer E
SE
Goddard
William A
WA
D000818:Animals; D001665:Binding Sites; D006801:Humans; D007659:Ketones / Q000378:metabolism*; D051379:Mice; D010422:Pentanones / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018035:Receptors, Odorant / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D007659:Ketones; D010422:Pentanones; D018035:Receptors, Odorant; C009541:2-tridecanone; C076402:2-pentanone
J Neurosci. 2001 Aug 15;21(16):6018-25
11487625
Proc Natl Acad Sci U S A. 1984 Jan;81(1):140-4
6582470
J Am Chem Soc. 2002 Dec 4;124(48):14442-9
12452720
Nucleic Acids Res. 2003 Jul 15;31(14):3982-92
12853614
Science. 1998 Jan 9;279(5348):237-42
9422698
Eur J Neurosci. 2002 Feb;15(3):409-18
11876768
J Mol Biol. 1997 Apr 18;267(5):1268-82
9150411
Science. 1999 Oct 22;286(5440):707-11
10531047
Proteins. 2003 Feb 1;50(2):213-21
12486715
Chem Senses. 2000 Apr;25(2):155-65
10781022
Hum Mol Genet. 1998 Sep;7(9):1337-45
9700185
Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):10712-6
11005853
J Mol Biol. 1982 Oct 25;161(2):269-88
7154081
Biophys J. 2004 Apr;86(4):1904-21
15041637
Protein Sci. 2004 Jan;13(1):240-54
14691239
Chem Senses. 1996 Dec;21(6):773-91
8985605
Chem Senses. 2004 Sep;29(7):595-616
15337685
Cell. 1999 Mar 5;96(5):713-23
10089886
Eye (Lond). 1998;12 ( Pt 3b):504-10
9775210
J Mol Biol. 1990 Oct 5;215(3):403-10
2231712
Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2736-41
14981238
Nat Neurosci. 2000 Dec;3(12):1248-55
11100145
Mamm Genome. 1999 Dec;10(12):1172-4
10594242
Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2636-41
11880618
Proteins. 1994 Nov;20(3):227-47
7892172
Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12622-7
12351677
J Phys Chem B. 1998 Apr 30;102(18):3586-616
24889800
J Neurosci. 2002 Apr 15;22(8):3033-43
11943806
J Med Chem. 2004 Jan 1;47(1):56-71
14695820
Cell. 1998 Dec 23;95(7):917-26
9875846
J Comput Aided Mol Des. 2000 May;14(4):383-401
10815774
Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3815-20
14999101
Cell. 1991 Apr 5;65(1):175-87
1840504
Nat Neurosci. 2002 Feb;5(2):124-33
11802173
Nat Neurosci. 2004 Apr;7(4):337-8
15034588
Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2156-61
14769939
Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2584-9
14983052
Chem Senses. 2004 May;29(4):269-90
15150141