Study of adenylyl cyclase-GαS interactions and identification of novel AC ligands

Mol Cell Biochem. 2018 Sep;446(1-2):63-72. doi: 10.1007/s11010-018-3273-4.

Appalaraju Jaggupilli ¹ ², Premnath Dhanaraj ¹ ², Alexander Pritchard ¹ ³, John L Sorensen ¹ ³, Shyamala Dakshinamurti ¹ ⁴ ⁵, Prashen Chelikani ⁶ ⁷ ⁸ ⁹

Affiliations

1 Manitoba Chemosensory Biology (MCSB) Research Group, Winnipeg, MB, R3E 0W4, Canada.
2 Department of Oral Biology, University of Manitoba, Winnipeg, MB, R3E 0W4, Canada.
3 Department of Chemistry, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada.
4 Departments of Pediatrics, Physiology, University of Manitoba, Winnipeg, MB, R3E 0W4, Canada.
5 Biology of Breathing, Children's Hospital Research Institute of Manitoba (CHRIM), Winnipeg, MB, R3E 3P4, Canada.
6 Manitoba Chemosensory Biology (MCSB) Research Group, Winnipeg, MB, R3E 0W4, Canada. Prashen.Chelikani@umanitoba.ca.
7 Department of Oral Biology, University of Manitoba, Winnipeg, MB, R3E 0W4, Canada. Prashen.Chelikani@umanitoba.ca.
8 Biology of Breathing, Children's Hospital Research Institute of Manitoba (CHRIM), Winnipeg, MB, R3E 3P4, Canada. Prashen.Chelikani@umanitoba.ca.
9 Department of Oral Biology, and Manitoba Chemosensory Biology (MCSB) Research Group, D319, University of Manitoba, Winnipeg, MB, R3E 0W4, Canada. Prashen.Chelikani@umanitoba.ca.

PMID: 29327289 DOI: 10.1007/s11010-018-3273-4

Abstract

Adenylyl cyclases (ACs) are membrane bound Enzymes that catalyze the production of cAMP from ATP in response to the activation by G-protein Gαs. Different isoforms of ACs are ubiquitously expressed in different tissues involved in regulatory mechanisms in response to specific stimulants. There are 9 AC isoforms present in humans, with AC5 and AC6 proposed to play a vital role in cardiac functions. The activity of AC6 is sensitive to nitric oxide, such that nitrosylation of the protein might regulate its function. However, the information on structural determinants of nitrosylation in ACs and how they interact with Gαs is limited. Here we used homology modeling to build a molecular model of human AC6 bound to Gαs. Based on this 3D model, we predict the nitrosylation amenable cysteines, and identify potential novel ligands of AC6 using virtual ligand screening. Our model suggests Cys1004 in AC6 (subunit C2) and Cys174 in Gαs present at the AC-Gαs interface as the possible residues that might undergo reversible nitrosylation. Docking analysis predicted novel ligands of AC6 that include forskolin-based compounds and its derivatives. Further work involving site-directed mutagenesis of the predicted residues will allow manipulation of AC activity using novel ligands, and crucial insights on the role of nitrosylation of these proteins in pathophysiological conditions.

Keywords

Adenylyl cyclase (AC); Cyclic adenosine monophosphate (cAMP); Forskolin; Ligand screening; Nitric oxide (NO); Protein modeling.

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