Two different domain swapped dimer structures were revealed by crystal structure of EPIC1 from Phytophthora nicotianae.

Cysteine protease inhibitors such as cystatins are crucial regulators of proteolytic activity involved in immunity, host-pathogen interactions, and cellular homeostasis. EPIC1, a cystatin-like inhibitor secreted by plant pathogen, such as Phytophthora nicotianae, suppresses host immunity by targeting papain-like cysteine proteases. Here, we report the high-resolution crystal structure of EPIC1, revealing a domain-swapped dimer architecture in which structural elements are exchanged between monomers. Notably, we identified two distinct types of domain-swapped dimers, both stabilized by interdomain disulfide bonds-an unprecedented feature among pathogen-derived cystatin-like inhibitors. These covalent linkages are predicted to play a critical role in dimer formation and structural integrity. Our findings provide the first atomic-resolution structure of EPIC1 and uncover a novel dimerization mechanism that may contribute to its functional stability and specificity in the host environment.