8CP0

Structure of the catalytic domain of P. vivax Sub1 (trigonal crystal form)

8CP0 の概要

• エントリーDOI: 10.2210/pdb8cp0/pdb
• 関連するPDBエントリー: 8coz
• 分子名称: subtilisin, CALCIUM ION (2 entities in total)
• 機能のキーワード: plasmodium, serine protease, drug target, malaria, hydrolase
• 由来する生物種: Plasmodium vivax (malaria parasite P. vivax)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43714.03

構造登録者

Martinez, M.,Bouillon, A.,Batista, F.,Alzari, P.M.,Barale, J.C.,Haouz, A. (登録日: 2023-03-01, 公開日: 2023-07-19, 最終更新日: 2023-11-22)

主引用文献

Martinez, M.,Batista, F.A.,Maurel, M.,Bouillon, A.,Ortega Varga, L.,Wehenkel, A.M.,Le Chevalier-Sontag, L.,Blondel, A.,Haouz, A.,Hernandez, J.F.,Alzari, P.M.,Barale, J.C.
3D structures of the Plasmodium vivax subtilisin-like drug target SUB1 reveal conformational changes to accommodate a substrate-derived alpha-ketoamide inhibitor.
Acta Crystallogr D Struct Biol, 79:721-734, 2023

PubMed Abstract: The constant selection and propagation of multi-resistant Plasmodium sp. parasites require the identification of new antimalarial candidates involved in as-yet untargeted metabolic pathways. Subtilisin-like protease 1 (SUB1) belongs to a new generation of drug targets because it plays a crucial role during egress of the parasite from infected host cells at different stages of its life cycle. SUB1 is characterized by an unusual pro-region that tightly interacts with its cognate catalytic domain, thus precluding 3D structural analysis of enzyme-inhibitor complexes. In the present study, to overcome this limitation, stringent ionic conditions and controlled proteolysis of recombinant full-length P. vivax SUB1 were used to obtain crystals of an active and stable catalytic domain (PvS1) without a pro-region. High-resolution 3D structures of PvS1, alone and in complex with an α-ketoamide substrate-derived inhibitor (MAM-117), showed that, as expected, the catalytic serine of SUB1 formed a covalent bond with the α-keto group of the inhibitor. A network of hydrogen bonds and hydrophobic interactions stabilized the complex, including at the P1' and P2' positions of the inhibitor, although P' residues are usually less important in defining the substrate specificity of subtilisins. Moreover, when associated with a substrate-derived peptidomimetic inhibitor, the catalytic groove of SUB1 underwent significant structural changes, particularly in its S4 pocket. These findings pave the way for future strategies for the design of optimized SUB1-specific inhibitors that may define a novel class of antimalarial candidates.

PubMed: 37428845
DOI: 10.1107/S2059798323004710

実験手法

X-RAY DIFFRACTION (3.251 Å)