3IUQ
apPEP_D622N+PP closed state
Summary for 3IUQ
| Entry DOI | 10.2210/pdb3iuq/pdb |
| Related | 3IUJ 3IUL 3IUM 3IUN 3IUR 3IVM |
| Related PRD ID | PRD_000692 |
| Descriptor | Prolyl Endopeptidase, N-BENZYLOXYCARBONYL-L-PROLYL-L-PROLINAL, GLYCEROL, ... (4 entities in total) |
| Functional Keywords | prolyl endopeptidase, hydrolase |
| Biological source | Aeromonas punctata (Aeromonas caviae) |
| Total number of polymer chains | 1 |
| Total formula weight | 77634.15 |
| Authors | Chiu, T.K. (deposition date: 2009-08-31, release date: 2010-05-05, Last modification date: 2023-09-06) |
| Primary citation | Li, M.,Chen, C.,Davies, D.R.,Chiu, T.K. Induced-fit mechanism for prolyl endopeptidase J.Biol.Chem., 285:21487-21495, 2010 Cited by PubMed Abstract: Prolyl peptidases cleave proteins at proline residues and are of importance for cancer, neurological function, and type II diabetes. Prolyl endopeptidase (PEP) cleaves neuropeptides and is a drug target for neuropsychiatric diseases such as post-traumatic stress disorder, depression, and schizophrenia. Previous structural analyses showing little differences between native and substrate-bound structures have suggested a lock-and-key catalytic mechanism. We now directly demonstrate from seven structures of Aeromonus punctata PEP that the mechanism is instead induced fit: the native enzyme exists in a conformationally flexible opened state with a large interdomain opening between the beta-propeller and alpha/beta-hydrolase domains; addition of substrate to preformed native crystals induces a large scale conformational change into a closed state with induced-fit adjustments of the active site, and inhibition of this conformational change prevents substrate binding. Absolute sequence conservation among 28 orthologs of residues at the active site and critical residues at the interdomain interface indicates that this mechanism is conserved in all PEPs. This finding has immediate implications for the use of conformationally targeted drug design to improve specificity of inhibition against this family of proline-specific serine proteases. PubMed: 20444688DOI: 10.1074/jbc.M109.092692 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
Download full validation report
