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Crystal structure and ligandability of the 14-3-3/pyrin interface

DOI: 10.1016/j.bbrc.2023.02.013 DOI Help

Authors: Roxanne Lau (Technische Universiteit Eindhoven) , Michael M. Hann (GSK Medicines Research) , Christian Ottmann (Technische Universiteit Eindhoven)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochemical And Biophysical Research Communications , VOL 10

State: Published (Approved)
Published: February 2023

Open Access Open Access

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.

Journal Keywords: Protein-protein interactions; Fragments; Molecular glues; Small-molecule drug discovery; X-ray crystallography

Subject Areas: Biology and Bio-materials


Other Facilities: DESY PETRA III

Added On: 07/02/2023 14:54


Discipline Tags:

Non-Communicable Diseases Autoimmune Diseases Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)