Structures of human peptidylarginine deiminase type III provide insights into substrate recognition and inhibitor design
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Authors
Funabashi, KazumasaSawata, Mizuki
Nagai, Anna
Akimoto, Megumi
Mashimo, Ryutaro
Takahara, Hidenari
Kizawa, Kenji
Thompson, Paul R
Ite, Kenji
Kitanishi, Kenichi
Unno, Masaki
Document Type
Journal ArticlePublication Date
2021-05-07Keywords
CitrullineInhibitor
Isozyme
Post-translational modification
Quarternary structure
Selectivity
Amino Acids, Peptides, and Proteins
Biochemistry
Biophysics
Enzymes and Coenzymes
Medicinal-Pharmaceutical Chemistry
Structural Biology
Metadata
Show full item recordAbstract
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.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
DOI
10.1016/j.abb.2021.108911Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29783PubMed ID
33971157Related Resources
ae974a485f413a2113503eed53cd6c53
10.1016/j.abb.2021.108911