7R1O

p62-ZZ domain of the human sequestosome in complex with dusquetide

This is a non-PDB format compatible entry.

Summary for 7R1O

• Entry DOI: 10.2210/pdb7r1o/pdb
• Descriptor: Sequestosome-1, Dusquetide, ZINC ION, ... (4 entities in total)
• Functional Keywords: dusquetide, p62, zz domain, idr, innate immune response, signalling protein, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 24561.19

Authors

Hakansson, M.,Hansson, M.,Logan, D.T.,Rozek, A.,Donini, O. (deposition date: 2022-02-03, release date: 2022-05-18, Last modification date: 2024-06-19)

Primary citation

Zhang, Y.,Towers, C.G.,Singh, U.K.,Liu, J.,Hakansson, M.,Logan, D.T.,Donini, O.,Kutateladze, T.G.
Dusquetide modulates innate immune response through binding to p62.
Structure, 30:1055-, 2022

PubMed Abstract: SQSTM1/p62 is an autophagic receptor that plays a major role in mediating stress and innate immune responses. Preclinical studies identified p62 as a target of the prototype innate defense regulator (IDR); however, the molecular mechanism of this process remains unclear. Here, we describe the structural basis and biological consequences of the interaction of p62 with the next generation of IDRs, dusquetide. Both electrostatic and hydrophobic contacts drive the formation of the complex between dusquetide and the ZZ domain of p62. We show that dusquetide penetrates the cell membrane and associates with p62 in vivo. Dusquetide binding modulates the p62-RIP1 complex, increases p38 phosphorylation, and enhances CEBP/B expression without activating autophagy. Our findings provide molecular details underlying the IDR action that may help in the development of new strategies to pharmacologically target p62.

PubMed: 35640615
DOI: 10.1016/j.str.2022.05.003

Experimental method

X-RAY DIFFRACTION (2.202 Å)