PDBsum entry 6ic6

Hydrolase

PDB id: 6ic6

Contents

Protein chains

118 a.a.

162 a.a.

68 a.a.

Ligands

NAG-NAG-BMA-MAN-MAN

NAG ×2

H9B

Metals

_CL

Waters ×296

PDB id:

6ic6

Name:

Hydrolase

Title:

Human cathepsin-c in complex with cyclopropyl peptidyl nitrile inhibitor 1

Structure:

Dipeptidyl peptidase 1. Chain: a. Synonym: cathepsin c,cathepsin j,dipeptidyl peptidase i,dppi, dipeptidyl transferase. Engineered: yes. Dipeptidyl peptidase 1. Chain: b. Synonym: cathepsin c,cathepsin j,dipeptidyl peptidase i,dppi, dipeptidyl transferase.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ctsc, cppi. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Expression_system_cell_line: bti-tn-5b1-4. Expression_system_cell_line: bti-tn-5b1-4

Resolution:

1.90Å R-factor: 0.147 R-free: 0.186

Authors:

M.Hakansson,D.T.Logan,B.Korkmaz,A.Lesner,M.Wysocka,A.Gieldon, F.Gauthier,D.Jenne,C.Lauritzen,J.Pedersen

Key ref:

B.Korkmaz et al. (2019). 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. PubMed id: 30978322 DOI: 10.1016/j.bcp.2019.04.006

Date:

02-Dec-18 Release date: 24-Apr-19

Protein chain

P53634  (CATC_HUMAN) -  Dipeptidyl peptidase 1 from Homo sapiens

Seq: 463 a.a.

Struc: 118 a.a.

Protein chain

P53634  (CATC_HUMAN) -  Dipeptidyl peptidase 1 from Homo sapiens

Seq: 463 a.a.

Struc: 162 a.a.

Protein chain

P53634  (CATC_HUMAN) -  Dipeptidyl peptidase 1 from Homo sapiens

Seq: 463 a.a.

Struc: 68 a.a.

Enzyme reactions

• Enzyme class: Chains A, B, C: E.C.3.4.14.1 - dipeptidyl-peptidase I.
• Reaction: Release of an N-terminal dipeptide, Xaa-Xbb-|-Xcc, except when Xaa is Arg or Lys, or Xbb or Xcc is Pro.

DOI no: 10.1016/j.bcp.2019.04.006

Biochem Pharmacol 164:349-367 (2019)

PubMed id: 30978322

Structure-based design and in vivo anti-arthritic activity evaluation of a potent dipeptidyl cyclopropyl nitrile inhibitor of cathepsin C.

B.Korkmaz, A.Lesner, M.Wysocka, A.Gieldon, M.Håkansson, F.Gauthier, D.T.Logan, D.E.Jenne, C.Lauritzen, J.Pedersen.

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_XPZ-01 ((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_XPZ-01 accumulated in the bone marrow reaching levels suitable for CatC inhibition. Subcutaneous administration of IcatC_XPZ-01 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.