Papain-like protease

[2] Papain-like proteases share a common catalytic dyad active site featuring a cysteine amino acid residue that acts as a nucleophile.

The mature monomer structure is characteristically divided into two lobes or subdomains, known as the L-domain (N-terminal) and the R-domain (C-terminal), where the active site is located between them.

[3] The zymogen is still inactive due to the presence of a propeptide which functions as an inhibitor blocking access to the active site.

[1][3][11] Papain-like proteases have a catalytic dyad consisting of a cysteine and a histidine residue, which form an ion pair through their charged thiolate and imidazolium side chains.

[1] Cysteine cathepsins are also part of the normal life cycle of the unicellular parasite Leishmania, where they function as virulence factors.

[16] The enzyme and potential drug target cruzipain is important for the life cycle of the parasite Trypanosoma cruzi, which causes Chagas' disease.

[17] Members of the papain-like protease family play a number of important roles in plant development, including seed germination, leaf senescence, and responding to abiotic stress.

Papain-like proteases are involved in regulation of programmed cell death in plants, for example in tapetum during development of pollen.

[23] The papain-like protease family includes a number of protein domains that are found in large polyproteins expressed by RNA viruses.

[6][7] One such experimental antiviral medication, Jun12682, is being studied as a potential treatment for COVID-19, and it is believed to work by inhibiting SARS-CoV-2 papain-like protease (PLpro).

[25] The surface zone of SARS-CoV-2 PLpro participating in binding of cellular proteins can also be targeted by bioactive molecules, such as glycyrrhizinic acid, thus potentially preventing protein-protein complexation.

An early (1984) X-ray crystallography structure of the mature papain enzyme. The primarily alpha-helical L-domain is shown at left, while the beta-sheet-rich R-domain is shown at right. The catalytic residues are highlighted; cysteine (oxidized in this structure) in green and histidine in blue. A conserved disulfide bond is shown in cyan. From PDB : 9PAP ​. [ 9 ]
Human cathepsin K in complex with the covalent inhibitor odanacatib , shown in light blue with the covalently modified catalytic cysteine in green. Odanacatib was studied in clinical trials as a cathepsin K inhibitor for osteoporosis. [ 12 ]
X-ray crystallography structure of papain in complex with a cystatin protease inhibitor (orange) from the taro plant. The active site residues are highlighted (cysteine in green and histidine in blue). From PDB : 3IMA ​. [ 18 ]
X-ray crystallography structure of the papain-like protease (PLPro) domain from SARS-CoV-2 non-structural protein 3. The catalytic residues are highlighted with cysteine in green and histidine in blue. The blue sphere is a bound zinc ion. From PDB : 6WZU ​. [ 24 ]