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Title: Carbon chain shape selectivity by the mouse olfactory receptor OR-I7

Abstract

The rodent OR-I7 is an olfactory receptor exemplar activated by aliphatic aldehydes such as octanal. Normal alkanals shorter than heptanal bind OR-I7 without activating it and hence function as antagonists in vitro. We report a series of aldehydes designed to probe the structural requirements for aliphatic ligand chains too short to meet the minimum approximate 6.9 Å length requirement for receptor activation. Experiments using recombinant mouse OR-I7 expressed in heterologous cells show that in the context of short aldehyde antagonists, OR-I7 prefers binding aliphatic chains without branches, though a single methyl on carbon-3 is permitted. The receptor can accommodate a surprisingly large number of carbons (e.g. ten in adamantyl) as long as the carbons are part of a conformationally constrained ring system. A rhodopsin-based homology model of mouse OR-I7 docked with the new antagonists suggests that small alkyl branches on the alkyl chain sterically interfere with the hydrophobic residues lining the binding site, but branch carbons can be accommodated when tied back into a compact ring system like the adamantyl and bicyclo[2.2.2]octyl systems.

Authors:
 [1];  [2];  [3]; ORCiD logo [4];  [3]; ORCiD logo [3];  [3];  [2]; ORCiD logo [1]
  1. City College of New York, NY (United States); City Univ. (CUNY), NY (United States)
  2. Duke Univ. Medical Center, Durham, NC (United States)
  3. Yale Univ., New Haven, CT (United States)
  4. City College of New York, NY (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)
Sponsoring Org.:
USDOE
OSTI Identifier:
1543816
Resource Type:
Accepted Manuscript
Journal Name:
Organic and Biomolecular Chemistry
Additional Journal Information:
Journal Volume: 16; Journal Issue: 14; Journal ID: ISSN 1477-0520
Publisher:
Royal Society of Chemistry
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES; Chemistry

Citation Formats

Liu, Min Ting, Ho, Jianghai, Liu, Jason Karl, Purakait, Radhanath, Morzan, Uriel N., Ahmed, Lucky, Batista, Victor S., Matsunami, Hiroaki, and Ryan, Kevin. Carbon chain shape selectivity by the mouse olfactory receptor OR-I7. United States: N. p., 2018. Web. doi:10.1039/c8ob00205c.
Liu, Min Ting, Ho, Jianghai, Liu, Jason Karl, Purakait, Radhanath, Morzan, Uriel N., Ahmed, Lucky, Batista, Victor S., Matsunami, Hiroaki, & Ryan, Kevin. Carbon chain shape selectivity by the mouse olfactory receptor OR-I7. United States. doi:10.1039/c8ob00205c.
Liu, Min Ting, Ho, Jianghai, Liu, Jason Karl, Purakait, Radhanath, Morzan, Uriel N., Ahmed, Lucky, Batista, Victor S., Matsunami, Hiroaki, and Ryan, Kevin. Fri . "Carbon chain shape selectivity by the mouse olfactory receptor OR-I7". United States. doi:10.1039/c8ob00205c. https://www.osti.gov/servlets/purl/1543816.
@article{osti_1543816,
title = {Carbon chain shape selectivity by the mouse olfactory receptor OR-I7},
author = {Liu, Min Ting and Ho, Jianghai and Liu, Jason Karl and Purakait, Radhanath and Morzan, Uriel N. and Ahmed, Lucky and Batista, Victor S. and Matsunami, Hiroaki and Ryan, Kevin},
abstractNote = {The rodent OR-I7 is an olfactory receptor exemplar activated by aliphatic aldehydes such as octanal. Normal alkanals shorter than heptanal bind OR-I7 without activating it and hence function as antagonists in vitro. We report a series of aldehydes designed to probe the structural requirements for aliphatic ligand chains too short to meet the minimum approximate 6.9 Å length requirement for receptor activation. Experiments using recombinant mouse OR-I7 expressed in heterologous cells show that in the context of short aldehyde antagonists, OR-I7 prefers binding aliphatic chains without branches, though a single methyl on carbon-3 is permitted. The receptor can accommodate a surprisingly large number of carbons (e.g. ten in adamantyl) as long as the carbons are part of a conformationally constrained ring system. A rhodopsin-based homology model of mouse OR-I7 docked with the new antagonists suggests that small alkyl branches on the alkyl chain sterically interfere with the hydrophobic residues lining the binding site, but branch carbons can be accommodated when tied back into a compact ring system like the adamantyl and bicyclo[2.2.2]octyl systems.},
doi = {10.1039/c8ob00205c},
journal = {Organic and Biomolecular Chemistry},
number = 14,
volume = 16,
place = {United States},
year = {2018},
month = {3}
}

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