Department of Chemistry and Biochemistry, The City College of New York, New York, NY 10031, USA.
Department of Molecular Genetics and Microbiology, and Neurobiology, Duke Institute for Brain Sciences, Duke University Medical Center, Durham, NC 27710, USA.
Org Biomol Chem. 2018 Apr 4;16(14):2541-2548. doi: 10.1039/C8OB00205C.
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.
啮齿动物 OR-I7 是一种嗅觉受体范例，可被脂肪醛（如辛醛）激活。比庚醛短的普通链烷醛与 OR-I7 结合但不激活它，因此在体外作为拮抗剂起作用。我们报告了一系列醛，旨在探测对于脂肪配体链的结构要求，这些配体链太短，无法满足受体激活的最小近似 6.9 Å 长度要求。使用在异源细胞中表达的重组小鼠 OR-I7 进行的实验表明，在短链脂肪醛拮抗剂的情况下，OR-I7 优先与无支链的脂肪链结合，尽管在碳 3 上允许有一个甲基。只要碳原子是构象受限的环系统的一部分，该受体就可以容纳数量惊人的碳原子（例如，金刚烷基中的十个）。与新拮抗剂对接的基于视紫红质的同源模型表明，烷基链上的小烷基支链在空间上干扰了排列在结合位点的疏水性残基，但当它们系回到类似金刚烷基和二环[2.2.2]辛基系统的紧凑环系统中时，支链碳原子是可以容纳的。
