CRISPR‐Cas comprise adaptive immune systems against foreign nucleic acids in prokaryotes. However, little is known about how the expression of CRISPR‐Cas genes is regulated in response to viral infection. Type‐III CRISPR interference results in the production of cyclic oligoadenylate (cOA) second messengers, which are known to bind various CRISPR Associated Rossmann Fold (CARF) ‐containing nuclease receptors to regulate their functions. Despite conservation of the CARF domain across Csa3 transcription factors, the basis for cOA binding specificity was unclear. In this study, we extend the known receptor repertoire of cOAs to include transcriptional factors by demonstrating specific binding of cA4 to Saccharolobus solfataricus Csa3 (Csa3Sso) (KD of 5.8 ± 0.03 μM). We determined a 2.0 Å resolution X‐ray crystal structure of cA4‐bound Csa3Sso, which reveals the binding of the Csa3Sso CARF domain to an elongated conformation of cA4. Binding affinity analyses of Csa3Sso mutants targeting the observed Csa3Sso•cA4 structural interface identified Csa3Sso residues that are required for ligand binding and specificity. We determined an essential role of a conserved glutamate (Glu122) for the low affinity interaction with cA4; a mutation of this residue to Ala and Gln resulted in a ~145 and ~125‐fold increase in cA4 binding affinity by Csa3Sso. Our complementary SAXS analyses detected a cA4‐induced conformational change in Csa3Sso, involving an asymmetric quaternary rearrangement of the C‐terminal winged helix‐turn‐helix (wHTH) domains supporting an allosteric mode of Csa3 regulation by cA4. Overall, our results support cA4 and Csa3‐mediated cross‐talk between type‐III and type‐I CRISPR systems that co‐exist in several prokaryotes.