Comparison of physicochemically conserved residues of human odorant receptors within two classes

Abstract

Human ORs included in class A GPCRs are phylogenetically divided into two clusters (Class I and Class II ORs) by their sequence identity. Interestingly, odorants that these classes each respond to seem to have different physicochemical features. Experimentally tested agonists of class I ORs tend to be more hydrophilic than those of class II ORs. Therefore, comparing the amino acid sequences of ORs within the classes may allow us to elucidate the structure-function relationships in ORs further. However, no study applied the physicochemical conservation analysis on the comparison of OR classes, which may provide more information about the structure. To extract factors that may distinguish the structures of ORs within the classes, we analyzed amino acid sequences of ORs within two classes in humans. Conserved residues from the analysis were classified into three different groups by conservation pattern in each class. We found that conservation profiles by structural regions in each class are different. To verify if these residues functionally distinguish the structures of ORs within two classes, two physicochemically differently conserved within the classes (PDCC) residues are experimentally tested by molecular dynamics simulations and expression on heterologous systems. The structure and the response of ORs by their agonist were changed significantly when the physicochemical feature in the residues was mutated by the one in the other class.