AI Article Synopsis
- Overactivation of Pyrin leads to inflammatory diseases like Mediterranean Fever and PAAND.
- Binding of 14-3-3 proteins reduces Pyrin's inflammation, suggesting that stabilizing this complex with small molecules could be therapeutic.
- Crystal structures reveal that the 14-3-3/PyrinpS242 complex is more favorable for small-molecule binding compared to the 14-3-3/PyrinpS208 complex, showing promise for drug development.
Article Abstract
Overactivation of Pyrin is the cause of the inflammatory diseases Mediterranean Fever and Pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). Binding of 14-3-3 proteins reduces the pro-inflammatory activity of Pyrin, hence small molecules that stabilize the Pyrin/14-3-3 complex could convey an anti-inflammatory effect. We have solved the atomic resolution crystal structures of phosphorylated peptides derived from PyrinpS208 and PyrinpS242 - the two principle 14-3-3 binding sites in Pyrin - in complex with 14-3-3 and analyzed the ligandability of these protein-peptide interfaces by crystal-based fragment soaking. The complex between 14-3-3 and PyrinpS242 appears to be much more amenable for small-molecule binding than that of 14-3-3/PyrinpS208. Consequently, only for the 14-3-3/PyrinpS242 complex could we find an interface-binding fragment, validating protein crystallography and fragment soaking as a method to evaluate the ligandability of protein surfaces.
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| http://dx.doi.org/10.1016/j.bbrc.2023.02.013 | DOI Listing |
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