8R8U

Human PADI4 in complex with cyclic peptide PADI4_3

Summary for 8R8U

• Entry DOI: 10.2210/pdb8r8u/pdb
• EMDB information: 19011
• Descriptor: Protein-arginine deiminase type-4, Cyclic Peptide PADI4_3, CALCIUM ION (3 entities in total)
• Functional Keywords: padi4, peptidyl arginine deiminase, cyclic peptide, cytosolic protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 153540.21

Authors

Benton, D.J.,Bertran, M.T.,Walport, L.J. (deposition date: 2023-11-30, release date: 2024-11-27)

Primary citation

Bertran, M.T.,Walmsley, R.,Cummings, T.,Aramburu, I.V.,Benton, D.J.,Mora Molina, R.,Assalaarachchi, J.,Chasampalioti, M.,Swanton, T.,Joshi, D.,Federico, S.,Okkenhaug, H.,Yu, L.,Oxley, D.,Walker, S.,Papayannopoulos, V.,Suga, H.,Christophorou, M.A.,Walport, L.J.
A cyclic peptide toolkit reveals mechanistic principles of peptidylarginine deiminase IV regulation.
Nat Commun, 15:9746-9746, 2024

PubMed Abstract: Peptidylarginine deiminase IV (PADI4, PAD4) deregulation promotes the development of autoimmunity, cancer, atherosclerosis and age-related tissue fibrosis. PADI4 additionally mediates immune responses and cellular reprogramming, although the full extent of its physiological roles is unexplored. Despite detailed molecular knowledge of PADI4 activation in vitro, we lack understanding of its regulation within cells, largely due to a lack of appropriate systems and tools. Here, we develop and apply a set of potent and selective PADI4 modulators. Using the mRNA-display-based RaPID system, we screen >10 cyclic peptides for high-affinity, conformation-selective binders. We report PADI4_3, a cell-active inhibitor specific for the active conformation of PADI4; PADI4_7, an inert binder, which we functionalise for the isolation and study of cellular PADI4; and PADI4_11, a cell-active PADI4 activator. Structural studies with PADI4_11 reveal an allosteric binding mode that may reflect the mechanism that promotes cellular PADI4 activation. This work contributes to our understanding of PADI4 regulation and provides a toolkit for the study and modulation of PADI4 across (patho)physiological contexts.

PubMed: 39528459
DOI: 10.1038/s41467-024-53554-1

Experimental method

ELECTRON MICROSCOPY (3.1 Å)