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• W4377029161 abstract "<b>Abstract ID 26509</b> <b>Poster Board 564</b> The A₃ adenosine receptor (A₃AR) is a G_i protein-coupled receptor that is a therapeutic target for inflammatory diseases, ischemia, cancer, and chronic neuropathic pain. Direct agonists of the A₃AR have entered late-stage clinical trials for psoriasis and inflammatory liver diseases. Unlike agonists, positive allosteric modulators (PAM) enhance A₃AR signaling with spaciotemporal specificity and reduced side effect profiles. While several chemical classes have been reported to act as allosteric modulators, the lack of structural information for the A₃AR has limited their development. Exploiting known species differences in A₃AR PAM pharmacology, we employed a human (responding species)/mouse (non-responding species) chimeric receptor approach to localize the allosteric binding pocket for the imidazoquinolinamine derivative, LUF6000 (<i>N</i>-(3,4-dichlorophenyl)-2-cyclohexyl-1<i>H</i>-imidazo[4,5-c]quinolin-4-amine), responsible for enhancement of orthosteric agonist-induced [³⁵S]GTPgS binding and slowing of orthosteric agonist radioligand ([¹²⁵I]I-AB-MECA) dissociation. The regions identified from this initial screen included distal portions of transmembrane domain (TMD) 7 and Helix 8, with possible additional interactions with the distal TMD 1/intracellular loop 1 region. With this information in hand, induced fit docking was performed with LUF6000 utilizing a homology model of the A₃AR constructed from the structure of an activated A₁AR. LUF6000 was found to dock in several orientations, and a leading pose was selected based on consistency with structure-activity-relationship information gained from our prior work. The nearly planar imidazoquinoline ring system is predicted to lie parallel to the TMD segments, sandwiched between the “lower” (intramembrane) ends of TMDs 1 and 7. Side chains from several residues along TMD7 and Helix 8 are predicted to interact with the heterocyclic scaffold of LUF6000, the importance of which is currently being pursued. The 3,4-dichlorophenyl-4-amino group points outwards towards the lipid interface, whereas the 2-cyclohexyl group extends towards the intersection between TMD 7 and Helix 8. Notably, pi-pi stacking was predicted between a non-conserved Y284^7.55 (mouse = cysteine) at the tip of TMD7 and the conserved Y293^8.54within Helix 8. The model also predicted hydrogen bonding between Y293^8.54and the exo-cyclic nitrogen of LUF6000. Since prior SAR work showed that maximal allosteric activity of imidazoquinolinamine derivatives requires bulky hydrophobic substituents at the C-2 position, we hypothesized that this interaction might be necessary to complement a hydrophobic pocket required for LUF6000 binding. This binding mode was supported by mutagenesis experiments, wherein allosteric activity of LUF6000 was completely lost when Y284^7.55 was mutated to a cysteine correlating with the mouse sequence or when Y293^8.54 was changed to a phenylalanine. Additional mutagenesis work ruled against the importance of potential disulfide bridge formation between a non-conserved cysteine in TMD 1 (C35^1.55) predicted to be in proximity to another non-conserved cysteine in Helix 8 (C300^8.61). This work is the first to provide molecular information on potential binding interactions of a PAM for the A₃AR, which uniquely occurs within the distal portion of TMD7 and Helix 8. <b>Support/Funding Information:</b> NIDDK (ZIADK031117), NHLBI RO1 (HL133589), AHA (898217), NHLBI (1F31HL1600193-01A1)" @default.
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• W4377029161 date "2023-05-18" @default.
• W4377029161 modified "2023-10-17" @default.
• W4377029161 title "Directed Mutagenesis Studies Reveal Amino Acid Residues Responsible for A₃Adenosine Receptor Positive Allosteric Modulator Function" @default.
• W4377029161 doi "https://doi.org/10.1124/jpet.122.265090" @default.
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