8S6A

X-ray structure of Dishevelled 3 PDZ domain in a complex with a class III peptide ligand

Summary for 8S6A

• Entry DOI: 10.2210/pdb8s6a/pdb
• Descriptor: Segment polarity protein dishevelled homolog DVL-3, C8 peptide (3 entities in total)
• Functional Keywords: dishevelled, wnt signalling, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 24950.55

Authors

Komarek, J.,Barinka, C. (deposition date: 2024-02-26, release date: 2025-03-12, Last modification date: 2025-06-25)

Primary citation

Kumar, J.,Micka, M.,Komarek, J.,Klumpler, T.,Bystry, V.,Sprangers, R.,Barinka, C.,Bryja, V.,Tripsianes, K.
A class III ligand oscillates between internal and terminal binding modes as it engages with the Dishevelled PDZ domain.
Structure, 2025

PubMed Abstract: One of the largest domain-motif interactomes in human involves PSD-95/Discs-large/ZO-1 (PDZ) domains. The framework for understanding the PDZ interactome is well established; however the functional dynamics associated with PDZ-ligand interactions are poorly understood. Here, we report a dual PDZ-binding mode that ascribes unique dynamic features to class III ligand recognition. The crystal structure revealed that the PDZ domain can recognize either of the carboxylate moieties (terminal or internal) present in the class III ligand and laid out the register rules responsible for the dual recognition. Variants of the ligand designed to retain one or the other carboxylate of the native sequence were sufficient for PDZ binding. The conformational dynamics of PDZ probed by NMR relaxation dispersion experiments demonstrated that the class III ligand is shuffling binding modes as it engages with the PDZ domain. Our mechanistic findings reveal yet another aspect of PDZ binding plasticity specific to class III ligands.

PubMed: 40516532
DOI: 10.1016/j.str.2025.05.012

Experimental method

X-RAY DIFFRACTION (1.36 Å)