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. Author manuscript; available in PMC: 2016 Nov 26.
Published in final edited form as: Nature. 2015 Nov 9;527(7579):477–483. doi: 10.1038/nature15699

Figure 5. Discovery of GPR65 allosteric agonist and negative allosteric modulator.

Figure 5

Predicted interactions of BTB09089 (a), ZINC13684400 (b), ZINC62678696 (c) at GPR65. Overlaid ogerin (thin magenta lines) (a) or BTB09089 (thin blue lines) docking poses at GPR68 or GPR65 resectively (b–c). ZINC13684400 (30 μM) displayed GPR65 allosteric agonist activity at pH 8.40 but not at lower pH or in control cells (d, n=32 measurements). (e) ZINC13684400 as a GPR65 agonist at pH 8.40 (n=3). (f) ZINC62678696 shifts BTB09089 curves downward at pH 8.40 (n=4). Normalized results (d–f) are mean ± SEM and curves were analyzed using a 4-prarmeter logistic function (e) or a standard operational allosteric model (f). (g) Predicted ternary complex between GPR656, ZINC62678696 and BTB09089, detailed interactions (left) and overall orientation in the GPR65 structure (right).