6IC5
Human cathepsin-C in complex with dipeptidyl cyclopropyl nitrile inhibitor 2
Summary for 6IC5
| Entry DOI | 10.2210/pdb6ic5/pdb |
| Descriptor | Dipeptidyl peptidase 1, alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total) |
| Functional Keywords | cathepsin-c, cysteine protease, structure-based drug design, arthritis, hydrolase |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 41326.63 |
| Authors | Hakansson, M.,Logan, D.T.,Korkmaz, B.,Lesner, A.,Wysocka, M.,Gieldon, A.,Gauthier, F.,Jenne, D.,Lauritzen, C.,Pedersen, J. (deposition date: 2018-12-02, release date: 2019-04-24, Last modification date: 2024-11-06) |
| Primary citation | Korkmaz, B.,Lesner, A.,Wysocka, M.,Gieldon, A.,Hakansson, M.,Gauthier, F.,Logan, D.T.,Jenne, D.E.,Lauritzen, C.,Pedersen, J. Structure-based design and in vivo anti-arthritic activity evaluation of a potent dipeptidyl cyclopropyl nitrile inhibitor of cathepsin C. Biochem. Pharmacol., 164:349-367, 2019 Cited by PubMed Abstract: Cathepsin C (CatC) is a dipeptidyl-exopeptidase which activates neutrophil serine protease precursors (elastase, proteinase 3, cathepsin G and NSP4) by removing their N-terminal propeptide in bone marrow cells at the promyelocytic stage of neutrophil differentiation. The resulting active proteases are implicated in chronic inflammatory and autoimmune diseases. Hence, inhibition of CatC represents a therapeutic strategy to suppress excessive protease activities in various neutrophil mediated diseases. We designed and synthesized a series of dipeptidyl cyclopropyl nitrile compounds as putative CatC inhibitors. One compound, IcatC ((S)-2-amino-N-((1R,2R)-1-cyano-2-(4'-(4-methylpiperazin-1-ylsulfonyl)biphenyl-4-yl)cyclopropyl)butanamide)) was identified as a potent inhibitor of both human and rodent CatC. In mice, pharmacokinetic studies revealed that IcatC accumulated in the bone marrow reaching levels suitable for CatC inhibition. Subcutaneous administration of IcatC in a monoclonal anti-collagen antibody induced mouse model of rheumatoid arthritis resulted in statistically significant anti-arthritic activity with persistent decrease in arthritis scores and paw thickness. PubMed: 30978322DOI: 10.1016/j.bcp.2019.04.006 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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