9mdk | pdb_00009mdk

Crystal Structure of E64-inhibited C0362 (TDE_0362 [TDE0362] resi 205-647)

spinqualitylabelsall models 9mdk, resolution 1.93Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9mdk is a 1 chain structure with sequence from Treponema denticola. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.93Å Ligands: E64, EDO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q73QT1_TREDE Publication Abstract from PubMed Periodontal diseases afflict 20-50% of the global population and carry serious health and economic burdens. Chronic periodontitis is characterized by inflammation of the periodontal pocket caused by dysbiosis. This dysbiosis is coupled with an increase in the population of Treponema denticola, a spirochete bacterium with high mobility and invasivity mediated by a number of virulence factors. One such virulence factor is TDE0362, a multidomain protein with a carboxy-terminal papain-superfamily cysteine protease (C0362). Most papain-superfamily cysteine proteases are produced as proenzymes with a prodomain that interacts with the prosegment binding loop (PBL), requiring proteolytic processing for full activation. Previous studies have indicated that C0362 is not produced as a proenzyme, suggesting an alternative regulatory mechanism. We previously determined the crystal structure of C0362 captured in an inactive conformation with an oxidized catalytic cysteine and a disordered PBL. In this follow-up study, we evaluated the active-site architecture and the PBL in two mutant (Y559A and C412S) structures and an inhibitor-bound (E64) structure to provide insight into the role that the PBL plays in the generation of active enzyme. Our results implicate Tyr559 as playing a critical role in the transition of the enzyme to an active state. We subsequently utilized the structural information to generate models of C0362 bound to human complement factors C3 and C4. Collectively, our results provide insight into the regulatory mechanism and putative substrate-binding interfaces of C0362, highlighting avenues of further research towards inhibition of this essential virulence factor. Structural insights into the role of the prosegment binding loop in a papain-superfamily cysteine protease from Treponema denticola.,Clark ND, Li C, Malkowski MG Acta Crystallogr F Struct Biol Commun. 2025 Feb 1;81(Pt 2):53-61. doi: , 10.1107/S2053230X25000378. Epub 2025 Jan 23. PMID:39846228 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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