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

Liu, Min Ting; Ho, Jianghai; Liu, Jason Karl; Purakait, Radhanath; Morzan, Uriel N.; Ahmed, Lucky; Batista, Victor S.; Matsunami, Hiroaki; Ryan, Kevin

doi:10.1039/c8ob00205c

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

Journal Article · Fri Mar 23 00:00:00 EDT 2018 · Organic and Biomolecular Chemistry

DOI:https://doi.org/10.1039/c8ob00205c· OSTI ID:1543816

Liu, Min Ting ^[1]; Ho, Jianghai ^[2]; Liu, Jason Karl ^[3]; ^[4]; Morzan, Uriel N. ^[3]; ^[3]; Batista, Victor S. ^[3]; Matsunami, Hiroaki ^[2]; ^[1]

City College of New York, NY (United States); City Univ. (CUNY), NY (United States)
Duke Univ. Medical Center, Durham, NC (United States)
Yale Univ., New Haven, CT (United States)
City College of New York, NY (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Organization:: USDOE

OSTI ID:: 1543816

Journal Information:: Organic and Biomolecular Chemistry, Journal Name: Organic and Biomolecular Chemistry Journal Issue: 14 Vol. 16; ISSN OBCRAK; ISSN 1477-0520

Publisher:: Royal Society of ChemistryCopyright Statement

Country of Publication:: United States

Language:: English

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