University of Massachusetts Medical School Faculty Publications

Title

Structures of human peptidylarginine deiminase type III provide insights into substrate recognition and inhibitor design

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Thompson Lab

Publication Date

2021-05-07

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Biochemistry | Biophysics | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Structural Biology

Abstract

Peptidylarginine deiminase type III (PAD3) is an isozyme belonging to the PAD enzyme family that converts arginine to citrulline residue(s) within proteins. PAD3 is expressed in most differentiated keratinocytes of the epidermis and hair follicles, while S100A3, trichohyalin, and filaggrin are its principal substrates. In this study, the X-ray crystal structures of PAD3 in six states, including its complex with the PAD inhibitor Cl-amidine, were determined. This structural analysis identified a large space around Gly374 in the PAD3-Ca(2+)-Cl-amidine complex, which may be used to develop novel PAD3-selective inhibitors. In addition, similarities between PAD3 and PAD4 were found based on the investigation of PAD4 reactivity with S100A3 in vitro. A comparison of the structures of PAD1, PAD2, PAD3, and PAD4 implied that the flexibility of the structures around the active site may lead to different substrate selectivity among these PAD isozymes.

Keywords

Citrulline, Inhibitor, Isozyme, Post-translational modification, Quarternary structure, Selectivity

DOI of Published Version

10.1016/j.abb.2021.108911

Source

Funabashi K, Sawata M, Nagai A, Akimoto M, Mashimo R, Takahara H, Kizawa K, Thompson PR, Ite K, Kitanishi K, Unno M. Structures of human peptidylarginine deiminase type III provide insights into substrate recognition and inhibitor design. Arch Biochem Biophys. 2021 May 7:108911. doi: 10.1016/j.abb.2021.108911. Epub ahead of print. PMID: 33971157. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Archives of biochemistry and biophysics

PubMed ID

33971157

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