HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Research Data Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hummel, P. Articles by Goddard, W. A. Search for Related Content PubMed PubMed Citation Articles by Hummel, P. Articles by Goddard, W. A., III Social Bookmarking                   What's this?

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

Materials and Process Simulation Center, California Institute of Technology, Pasadena, California 91125, USA

(RECEIVED September 15, 2004; FINAL REVISION November 2, 2004; ACCEPTED November 2, 2004)

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 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 E_BindThresh = 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.

Keywords: mOR912-93; hOR912-93; olfactory receptor; MembStruk; HierDock; odorant binding; structure; protein folding; Binding Threshold Hypothesis

Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.041119705.

Reprint requests to: William A. Goddard III, Materials and Process Simulation Center (MC 139-74), California Institute of Technology, Pasadena, CA 91125, USA; e-mail: wag{at}wag.caltech.edu; fax: (626) 585-0918.

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				W. A. Goddard III and R. Abrol 3-Dimensional Structures of G Protein-Coupled Receptors and Binding Sites of Agonists and Antagonists J. Nutr., June 1, 2007; 137(6): 1528S - 1538S. [Abstract] [Full Text] [PDF]

				C. L. McClendon, N. Vaidehi, V. W. T. Kam, D. Zhang, and W. A. Goddard III Fidelity of seryl-tRNA synthetase to binding of natural amino acids from HierDock first principles computations Protein Eng. Des. Sel., May 1, 2006; 19(5): 195 - 203. [Abstract] [Full Text] [PDF]

				P. Spijker, N. Vaidehi, P. L. Freddolino, P. A. J. Hilbers, and W. A. Goddard III Dynamic behavior of fully solvated beta2-adrenergic receptor, embedded in the membrane with bound agonist or antagonist PNAS, March 28, 2006; 103(13): 4882 - 4887. [Abstract] [Full Text] [PDF]