8D7K

Bifunctional Inhibition of Neutrophil Elastase and Cathepsin G by Eap2 from S. aureus

これはPDB形式変換不可エントリーです。

8D7K の概要

• エントリーDOI: 10.2210/pdb8d7k/pdb
• 関連するPDBエントリー: 8D4Q 8D4S 8D4U 8D4V 8D7I
• 分子名称: Cathepsin G, C-terminal truncated form, Extracellular Adherence Protein, Neutrophil elastase (3 entities in total)
• 機能のキーワード: protease inhibitor, immune evasion, neutrophil, s. aureus, protein binding, hydrolase-inhibitor, protein binding complex, hydrolase/inhibitor
• 由来する生物種: Staphylococcus aureus subsp. aureus; 詳細
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 238958.12

構造登録者

Gido, C.D.,Herdendorf, T.J.,Geisbrecht, B.V. (登録日: 2022-06-07, 公開日: 2023-06-14, 最終更新日: 2024-10-23)

主引用文献

Mishra, N.,Gido, C.D.,Herdendorf, T.J.,Hammel, M.,Hura, G.L.,Fu, Z.Q.,Geisbrecht, B.V.
S. aureus Eap is a polyvalent inhibitor of neutrophil serine proteases.
J.Biol.Chem., 300:107627-107627, 2024

PubMed Abstract: Staphylococcus aureus expresses three high-affinity neutrophil serine protease (NSP) inhibitors known as the extracellular adherence protein domain (EAPs) proteins. Whereas EapH1 and EapH2 are comprised of a single EAP domain, the modular extracellular adherence protein (Eap) from S. aureus strain Mu50 consists of four EAP domains. We recently reported that EapH2 can simultaneously bind and inhibit cathepsin-G (CG) and neutrophil elastase (NE), which are the two most abundant NSPs. This unusual property of EapH2 arises from independent CG and NE-binding sites that lie on opposing faces of its EAP domain. Here we used X-ray crystallography and enzyme assays to show that all four individual domains of Eap (i.e. Eap1, Eap2, Eap3, and Eap4) exhibit an EapH2-like ability to form ternary complexes with CG and NE that inhibit both enzymes simultaneously. We found that Eap1, Eap2, and Eap3 have similar functional profiles insofar as NSP inhibition is concerned but that Eap4 displays an unexpected ability to inhibit two NE enzymes simultaneously. Using X-ray crystallography, we determined that this second NE-binding site in Eap4 arises through the same region of its EAP domain that also comprises its CG-binding site. Interestingly, small angle X-ray scattering data showed that stable tail-to-tail dimers of the NE/Eap4/NE ternary complex exist in solution. This arrangement is compatible with NSP-binding at all available sites in a two-domain fragment of Eap. Together, our work implies that Eap is a polyvalent inhibitor of NSPs. It also raises the possibility that higher-order structures of NSP-bound Eap may have unique functional properties.

PubMed: 39098536
DOI: 10.1016/j.jbc.2024.107627

実験手法

X-RAY DIFFRACTION (3.1 Å)