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-Ca²⁺-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.

肽基精氨酸脱亚胺酶 III 型 (PAD3) 是属于 PAD 酶家族的同工酶，可将蛋白质内的精氨酸转化为瓜氨酸残基。PAD3 在表皮和毛囊的大多数分化角质形成细胞中表达，而 S100A3、透明质蛋白和丝聚蛋白是其主要底物。在这项研究中，确定了六种状态的 PAD3 的 X 射线晶体结构，包括其与 PAD 抑制剂 Cl-脒的复合物。该结构分析确定了 PAD3-Ca ^{2+ 中}Gly374 周围的大空间-Cl-脒复合物，可用于开发新型 PAD3 选择性抑制剂。此外，基于 PAD4 与 S100A3 体外反应性的研究，发现了 PAD3 和 PAD4 之间的相似性。PAD1、PAD2、PAD3 和 PAD4 结构的比较表明，活性位点周围结构的灵活性可能导致这些 PAD 同工酶之间的底物选择性不同。