1CS8

CRYSTAL STRUCTURE OF PROCATHEPSIN L

Summary for 1CS8

• Entry DOI: 10.2210/pdb1cs8/pdb
• Related: 1CJL
• Descriptor: HUMAN PROCATHEPSIN L (2 entities in total)
• Functional Keywords: prosegment, propeptide, inhibition, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Lysosome: P07711
• Total number of polymer chains: 1
• Total formula weight: 35920.97

Authors

Cygler, M.,Coulombe, R. (deposition date: 1999-08-17, release date: 1999-08-23, Last modification date: 2021-11-03)

Primary citation

Coulombe, R.,Grochulski, P.,Sivaraman, J.,Menard, R.,Mort, J.S.,Cygler, M.
Structure of human procathepsin L reveals the molecular basis of inhibition by the prosegment.
EMBO J., 15:5492-5503, 1996

PubMed Abstract: Cathepsin L is a member of the papain superfamily of cysteine proteases and, like many other proteases, it is synthesized as an inactive proenzyme. Its prosegment shows little homology to that of procathepsin B, whose structure, the first for a cysteine protease proenzyme, has been determined recently. We report here the 3-D structure of a mutant of human procathepsin L determined at 2.2 A resolution, describe the mode of binding employed by the prosegment and discuss the molecular basis for other possible roles of the prosegment. The N-terminal part of the prosegment is globular and contains three alpha-helices with a small hydrophobic core built around aromatic side chains. This domain packs against a loop on the enzyme's surface, with the aromatic side chain from the prosegment being located in the center of this loop and providing a large contact area. The C-terminal portion of the prosegment assumes an extended conformation and follows along the substrate binding cleft toward the N-terminus of the mature enzyme. The direction of the prosegment in the substrate binding cleft is opposite to that of substrates. The previously described role of the prosegment in the interactions with membranes is supported by the structure of its N-terminal domain. The fold of the prosegment and the mechanism by which it inhibits the enzymatic activity of procathepsin L is similar to that observed in procathepsin B despite differences in length and sequence, suggesting that this mode of inhibition is common to all enzymes from the papain superfamily.

PubMed: 8896443

Experimental method

X-RAY DIFFRACTION (1.8 Å)