4AW9

Crystal structure of active legumain in complex with YVAD-CMK

Summary for 4AW9

• Entry DOI: 10.2210/pdb4aw9/pdb
• Related: 4AWA 4AWB 4FGU
• Related PRD ID: PRD_002086
• Descriptor: LEGUMAIN, ACE-TYR-VAL-ALA-ASP-CHLOROMETHYLKETONE, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: hydrolase-hydrolase inhibitor complex, cysteine protease, lysosomal, aep, substrate specificity, mhcii, antigen processing, cancer, hydrolase/hydrolase inhibitor
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 2
• Total formula weight: 33750.01

Authors

Dall, E.,Brandstetter, H. (deposition date: 2012-06-01, release date: 2013-06-26, Last modification date: 2020-07-29)

Primary citation

Dall, E.,Brandstetter, H.
Mechanistic and Structural Studies on Legumain Explain its Zymogenicity, Distinct Activation Pathways, and Regulation
Proc.Natl.Acad.Sci.USA, 110:10940-, 2013

PubMed Abstract: The cysteine protease legumain plays important functions in immunity and cancer at different cellular locations, some of which appeared conflicting with its proteolytic activity and stability. Here, we report crystal structures of legumain in the zymogenic and fully activated form in complex with different substrate analogs. We show that the eponymous asparagine-specific endopeptidase activity is electrostatically generated by pH shift. Completely unexpectedly, the structure points toward a hidden carboxypeptidase activity that develops upon proteolytic activation with the release of an activation peptide. These activation routes reconcile the enigmatic pH stability of legumain, e.g., lysosomal, nuclear, and extracellular activities with relevance in immunology and cancer. Substrate access and turnover is controlled by selective protonation of the S1 pocket (KM) and the catalytic nucleophile (kcat), respectively. The multibranched and context-dependent activation process of legumain illustrates how proteases can act not only as signal transducers but as decision makers.

PubMed: 23776206
DOI: 10.1073/PNAS.1300686110

Experimental method

X-RAY DIFFRACTION (2.2 Å)