9MDO
Crystal Structure of Y559A Prosegment Binding Loop Mutant of C0362 (TDE_0362 [TDE0362] resi 205-647)
Summary for 9MDO
| Entry DOI | 10.2210/pdb9mdo/pdb |
| Related | 9ARC 9MDK 9MDM |
| Descriptor | Bacterial Ig-like domain protein C0362, 1,2-ETHANEDIOL, CHLORIDE ION, ... (4 entities in total) |
| Functional Keywords | papain-superfamily cysteine protease, virulence factor, tde_0362, alpha/beta hydrolase, hydrolase |
| Biological source | Treponema denticola |
| Total number of polymer chains | 1 |
| Total formula weight | 56539.38 |
| Authors | |
| Primary citation | Clark, N.D.,Li, C.,Malkowski, M.G. Structural insights into the role of the prosegment binding loop in a papain-superfamily cysteine protease from Treponema denticola. Acta Crystallogr.,Sect.F, 81:53-61, 2025 Cited by PubMed Abstract: 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. PubMed: 39846228DOI: 10.1107/S2053230X25000378 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.02 Å) |
Structure validation
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